rs112735431

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PS1_ModeratePP2PP5BP4BS2

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 same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4810S) has been classified as Uncertain significance.

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:6U:2O: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 Likely_benign. 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

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RNF213. . Gene score misZ 2.3013 (greater than the threshold 3.09). Trascript score misZ 4.9274 (greater than threshold 3.09). GenCC has associacion of gene with Moyamoya disease 2.

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: {Pathogenic=4, Likely_pathogenic=1, Uncertain_significance=2}. 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.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF213	NM_001256071.3 linkuse as main transcript	c.14429G>A	p.Arg4810Lys	missense_variant	60/68	ENST00000582970.6
RNF213-AS1	NR_029376.1 linkuse as main transcript	n.240+29784C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF213	ENST00000582970.6 linkuse as main transcript	c.14429G>A	p.Arg4810Lys	missense_variant	60/68	1	NM_001256071.3	P2
RNF213-AS1	ENST00000575034.5 linkuse as main transcript	n.190+29784C>T		intron_variant, non_coding_transcript_variant		2

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:6Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Moyamoya disease 2

Pathogenic:4Uncertain:1Other:1

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. -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 24, 2022	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. -
risk factor, no assertion criteria provided	literature only	OMIM	Dec 01, 2012	- -
Likely pathogenic, no assertion criteria provided	research	Department of Internal Medicine, University of Texas Health Science Center at Houston	Sep 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2023	Also known as c.14576G>A or R4859K due to alternate nomenclature; The most common variant identified in the RNF213 gene in individuals of East Asian background and has been reported numerous times to confer susceptibility to moyamoya disease (PMID: 21799892, 21048783, 22377813, 26806063); Homozygosity has been associated with earlier age of onset of disease compared to heterozygous individuals (PMID: 22377813); 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 supports that this missense variant does not alter protein structure/function; 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, 25278557, 23970789, 21048783, 25817623, 26126547, 26590131, 26125557, 26806063, 27253870, 27128593, 28063898, 28506590, 28617845, 29500468, 28962888, 27365075, 27476341, 31060437, 29718794, 30922903, 30615506, 30562119, 30276334, 30992731, 31293503, 29567577, 31197213, 30947170, 31347299, 31542298, 34013582, 31589614, 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, 23994138, 26315378) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

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

MutationTaster

Benign

1.0

N;N;N

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