chr17-80385145-G-A

Position:

chr17-80385145-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PS1_ModeratePP5BP4BS1_Supporting

The NM_001256071.3(RNF213):c.14429G>A(p.Arg4810Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,614,200 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

RNF213
NM_001256071.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1O:1

Conservation

PhyloP100: 0.261

Variant links:

Genes affected

RNF213 (HGNC:14539): (ring finger protein 213) This gene encodes a protein containing a C3HC4-type RING finger domain, which is a specialized type of Zn-finger that binds two atoms of zinc and is thought to be involved in mediating protein-protein interactions. The protein also contains an AAA domain, which is associated with ATPase activity. This gene is a susceptibility gene for Moyamoya disease, a vascular disorder of intracranial arteries. This gene is also a translocation partner in anaplastic large cell lymphoma and inflammatory myofibroblastic tumor cases, where a t(2;17)(p23;q25) translocation has been identified with the anaplastic lymphoma kinase (ALK) gene on chromosome 2, and a t(8;17)(q24;q25) translocation has been identified with the MYC gene on chromosome 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

RNF213 links:

RNF213-AS1 (HGNC:54402): (RNF213 antisense RNA 1)

RNF213-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PS1

Transcript NM_001256071.3 (RNF213) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PP5

Variant 17-80385145-G-A is Pathogenic according to our data. Variant chr17-80385145-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39700.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=8, Likely_pathogenic=1}. Variant chr17-80385145-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.005629897). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000295 (45/152314) while in subpopulation SAS AF= 0.00642 (31/4828). AF 95% confidence interval is 0.00465. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF213	NM_001256071.3 link	c.14429G>A	p.Arg4810Lys	missense_variant	60/68	ENST00000582970.6	NP_001243000.2	Q63HN8A0A0A0MTR7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF213	ENST00000582970.6 link	c.14429G>A	p.Arg4810Lys	missense_variant	60/68	1	NM_001256071.3	ENSP00000464087.1		A0A0A0MTR7

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000262

AC:

AN:

251462

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00283

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000237

AC:

347

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

214

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00574

Gnomad4 SAS exome

AF:

0.00130

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000295

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000354

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Moyamoya disease 2

Pathogenic:5Uncertain:1Other:1

Likely pathogenic, no assertion criteria provided	research	Department of Internal Medicine, University of Texas Health Science Center at Houston	Sep 08, 2014	- -
risk factor, no assertion criteria provided	literature only	OMIM	Dec 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function and dominant negative have been reported (PMIDs: 26662949, 35135845). (I) 0108 - This gene is associated with susceptibility to moyamoya disease 2 (MIM#607151), with both recessive and dominant inheritance patterns have been reported, where recessive inheritance has earlier onset of symptoms (PMID: 26198278). (I) 0112 - The condition associated with this gene has incomplete penetrance. Low penetrance is well reported for the p.(Arg4810Lys) variant in this gene (PMID: 35605621). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 and v3: 104 heterozygotes, 1 homozygote). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 10 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been well-reported as an east Asian founder variant associated with moyamoya disease, however its penetrance is low (1 in 150) (PMIDs: 35605621, 35401401). It has been reported as heterozygous in many individuals with moyamoya disease, as homozygous in affected individuals with earlier ages of onset, and also as heterozygous in unaffected individuals (PMIDs: 35876407, 22377813). (SP) 1010 - Functional evidence for this variant is inconclusive. Functional studies using HeLa cells with this variant had wild type level of ATPase activity and retained oligomerisation activity, however they had a reduced autoubiquitylation activity (PMID: 35135845). Another study of the mouse isoform showed this variant did not affect poly-ubiquitination activity (PMID: 32573437). (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039700, 3billion dataset, PS1_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000240, PM2_M). The carrying of p. Arg4810Lys in RNF213 gene is closely related the MoyaMoya disease risk in an east asian (PMID 21799892, 25278557). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL:0.071<=0.4, 3CNET:0.018<=0.252, BP4_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 26, 2022	RNF213 NM_001256071.2 exon 60 p.Arg4810Lys (c.14429G>A): This variant was first identified as a founder variant common in East Asian patients with Moyamoyma disease (MMD) (Liu 2011 PMID: 21799892, Kamada 2011 PMID: 21048783). It has since been reported in the literature in numerous individuals with MMD in both the heterozygous and homozygous state, segregating with disease in several affected family members (Selected publications: Liu 2011 PMID:21799892, Miyatake 2012 PMID:22377813, Hitomi 2013 PMID:23850618, Cecchi 2014 PMID:25278557, Zhang 2017 PMID: 28063898, Zhang 2019 PMID:31290353). However, multiple unaffected family members have also been reported who carry this variant (Liu 2011 PMID: 21799892, Cecchi 2014 PMID:25278557), and it is present in 0.02% (32/143300) of all alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-80385145-G-A?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. Given the prevalence of this variant in unaffected and affected individuals with MMD, the odds ratio of this variant has been estimated to be 112 in East Asian populations (Liu 2011 PMID: 21799892). Functional studies have shown a deleterious effect of this variant, but these studies have not been replicated with in vivo mouse models (Hitomi 2013 PMID:23850618, Kanoke 2015 PMID: 26315378, Kobayashi 2015 PMID:26126547). However, these studies may not accurately represent in vivo biological function in humans. Evolutionary conservation suggests that this variant may not impact the protein, while computational predictive tools for this variant are unclear. This variant is also documented in ClinVar (Variation ID:39700). In summary, this variant is classified as a pathogenic risk allele given extensive published case-control data which suggests the involvement of other genetic and/or environmental factors. -
Uncertain significance, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Oct 26, 2024	Heterozygous missense variation in exon 61 of the RNF213 gene that result in the amino acid substitution of lysine for arginine at codon 4859 was detected. The observed variant has previously been reported in patient affected with Moyamoya disease and it lies in the glycosyl hydrolase family 20, catalytic domain of RNF213 protein. The p.Arg4859Lys variant has minor allele frequency of 0.1% and 0.02% in the 1000 genome and gnomAD database. In summary, the variant meets our criteria to be classified as variant of uncertain significance. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 4810 of the RNF213 protein (p.Arg4810Lys). This variant is present in population databases (rs112735431, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with autosomal dominant and recessive Moyamoya disease (PMID: 21048783, 21799892, 22377813, 22931863, 23110205). It is commonly reported in individuals of East Asian ancestry (PMID: 21799892, 26530418). ClinVar contains an entry for this variant (Variation ID: 39700). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNF213 function (PMID: 21799892, 26126547). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2024	Functional studies indicate that cells overexpressing R4810K have mitotic abnormalities and decreased angiogenesis, and a transgenic murine model showed that the R4810K variant inhibits angiogenesis in mice (PMID: 23994138, 23850618, 26126547); Other functional studies have shown that R4810K may not affect transcription levels or ubiquitination activity, and a knock-in murine model showed that mice harboring R4810K grew normally with no significant differences from wild type mice and no spontaneous development of moyamoya disease (PMID: 26315378, 21799892); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.14576G>A or R4859K due to alternate nomenclature; This variant is associated with the following publications: (PMID: 23110205, 25547042, 24029639, 26292667, 26530418, 25876583, 27375007, 25964206, 22878964, 25883833, 28414759, 29165161, 30925911, 33356381, 23850618, 22931863, 22377813, 22688066, 23970789, 21048783, 25817623, 26126547, 26590131, 26125557, 26806063, 27253870, 28063898, 28506590, 28617845, 29500468, 28962888, 27365075, 27476341, 31060437, 29718794, 30922903, 30615506, 30562119, 30276334, 30992731, 31293503, 29567577, 31197213, 30947170, 31347299, 31542298, 34013582, 31589614, 35640559, 36657715, 36063804, 38115307, 37768541, 37657303, 36916017, 37554039, 36147931, 37722316, 32434013, 34680863, 34749017, 34624841, 34716882, 35876407, 34335228, 36936868, 36324634, 32212963, 35231114, 34710878, 31908915, 35455046, 32088313, 32814565, 35701560, 35642380, 31818681, 31733606, 31949090, 32073714, 32369273, 32438004, 28931766, 33482763, 33055470, 33175469, 28619492, 32572006, 32686731, 33370357, 37137523, 35861108, 37269436, 21799892, 25278557, 23994138, 26315378, 37012328, 38927660, 27128593) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 25, 2024	BP4, PS3_supporting, PS4 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2024

The c.14576G>A (p.R4859K) alteration is located in exon 61 (coding exon 60) of the RNF213 gene. This alteration results from a G to A substitution at nucleotide position 14576, causing the arginine (R) at amino acid position 4859 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.024% (68/282860) total alleles studied. The highest observed frequency was 0.266% (53/19954) of East Asian alleles. This variant (also reported as p.R4810K in the literature) has been identified in the homozygous state and/or in conjunction with other variants in this same gene in individuals with features consistent with RNF213-related Moyamoya disease and segregated with disease in at least one family (Kamada, 2011; Liu, 2011). This is a commonly reported RNF213 founder variant in the East Asian population (Shoemaker, 2015; Huang, 2016). This amino acid position is poorly conserved in available vertebrate species. In multiple assays testing RNF213 function, this variant showed functionally indeterminant results. However, another assay suggests this variant alters angiogenesis under certain conditions; additional evidence is needed to confirm these findings (Liu 2011; Kobayashi 2015). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.4

DANN

Benign

0.84

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.071

Sift

Benign

0.17

T;.

Sift4G

Uncertain

0.034

D;D

Vest4

0.19

MVP

0.45

MPC

0.16

ClinPred

0.031

GERP RS

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over