17-80385145-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3PP5BP4

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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002495932: 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)." and additional evidence is available in ClinVar. 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:10U:2O:1

Conservation

PhyloP100: 0.261

Publications

442 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: Uncertain_significance. The variant received 4 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002495932: 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).; SCV001830948: 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).

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 VariationId is 39700.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF213	NM_001256071.3	MANE Select	c.14429G>A	p.Arg4810Lys	missense	Exon 60 of 68	NP_001243000.2	A0A0A0MTR7
RNF213	NM_001410195.1		c.14576G>A	p.Arg4859Lys	missense	Exon 61 of 69	NP_001397124.1	A0A0A0MTC1
RNF213	NM_020914.5		c.14576G>A	p.Arg4859Lys	missense	Exon 61 of 69	NP_065965.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF213	ENST00000582970.6	TSL:1 MANE Select	c.14429G>A	p.Arg4810Lys	missense	Exon 60 of 68	ENSP00000464087.1	A0A0A0MTR7
RNF213	ENST00000427003.7	TSL:1	n.543G>A		non_coding_transcript_exon	Exon 4 of 12
RNF213	ENST00000508628.6	TSL:5	c.14576G>A	p.Arg4859Lys	missense	Exon 61 of 69	ENSP00000425956.2	A0A0A0MTC1

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

GnomAD2 exomes

AF:

0.000262

AC:

AN:

251462

AF XY:

0.000258

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00574

AC:

228

AN:

39700

South Asian (SAS)

AF:

0.00130

AC:

112

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112004

Other (OTH)

AF:

0.0000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000295

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00270

AC:

AN:

5184

South Asian (SAS)

AF:

0.00642

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000354

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Moyamoya disease 2 (8)

not provided (4)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.4

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.030

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.53

M_CAP

Benign

0.0046

MetaRNN

Benign

0.0056

MetaSVM

Benign

-1.1

PhyloP100

0.26

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.8

REVEL

Benign

0.071

Sift

Benign

0.17

Sift4G

Uncertain

0.034

Vest4

0.19

MVP

0.45

MPC

0.16

ClinPred

0.031

GERP RS

2.0

Mutation Taster

=88/12

disease causing (ClinVar)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over