rs139265462

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS1

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. 11/19 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

Publications

18 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001256071.3

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 submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000571 (87/152362) while in subpopulation NFE AF = 0.00101 (69/68032). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF213	NM_001256071.3 link	c.12055C>T	p.Arg4019Cys	missense_variant	Exon 44 of 68	ENST00000582970.6	NP_001243000.2	Q63HN8A0A0A0MTR7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF213	ENST00000582970.6 link	c.12055C>T	p.Arg4019Cys	missense_variant	Exon 44 of 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

GnomAD2 exomes

AF:

0.000565

AC:

142

AN:

251476

AF XY:

0.000537

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 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

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000917

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000517

AC:

575

AN:

1112000

Other (OTH)

AF:

0.000596

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000571

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41584

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000739

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

Mar 03, 2017

UMR-S1161, Institut national de la santé et de la recherche médicale

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Sep 08, 2014

Department of Internal Medicine, University of Texas Health Science Center at Houston

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Uncertain:1Benign:1

Dec 20, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS4, PP2, PS3_supporting, PS4_moderate -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

0.57

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

Mutation Taster

=96/4

polymorphism

(source)

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

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rs139265462

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over