rs139265462

Positions:

chr17-80368043-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6

The NM_001256071.3(RNF213):c.12055C>T(p.Arg4019Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

RNF213
NM_001256071.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.574

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 (HGNC:):

RNF213 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.12797883).

BP6

Variant 17-80368043-C-T is Benign according to our data. Variant chr17-80368043-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210007.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF213	NM_001256071.3 linkuse as main transcript	c.12055C>T	p.Arg4019Cys	missense_variant	44/68	ENST00000582970.6	NP_001243000.2	Q63HN8A0A0A0MTR7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF213	ENST00000582970.6 linkuse as main transcript	c.12055C>T	p.Arg4019Cys	missense_variant	44/68	1	NM_001256071.3	ENSP00000464087.1		A0A0A0MTR7

Frequencies

GnomAD3 genomes

AF:

0.000571

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000565

AC:

142

AN:

251476

Hom.:

AF XY:

0.000537

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000510

AC:

746

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000561

AC XY:

408

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000917

Gnomad4 NFE exome

AF:

0.000517

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000571

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000738

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000544

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Moyamoya disease 2

Uncertain:2

Uncertain significance, no assertion criteria provided	research	UMR-S1161, Institut national de la santé et de la recherche médicale	Mar 03, 2017	- -
Uncertain significance, no assertion criteria provided	research	Department of Internal Medicine, University of Texas Health Science Center at Houston	Sep 08, 2014	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 20, 2023	BS4, PP2, PS3_supporting, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.70

T;T

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.13

T;T

MetaSVM

Uncertain

-0.057

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.4

D;.

REVEL

Uncertain

0.37

Sift

Benign

0.037

D;.

Sift4G

Uncertain

0.053

T;T

Vest4

0.25

MVP

0.60

MPC

0.67

ClinPred

0.14

GERP RS

-6.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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