chr17-80393361-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001256071.3(RNF213):​c.15487G>A​(p.Val5163Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

RNF213
NM_001256071.3 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.350
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-AS1 (HGNC:54402): (RNF213 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.042259544).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000164 (25/152140) while in subpopulation NFE AF= 0.000294 (20/68034). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 12 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 rank MANE Protein UniProt
RNF213NM_001256071.3 linkc.15487G>A p.Val5163Ile missense_variant Exon 68 of 68 ENST00000582970.6 NP_001243000.2 Q63HN8A0A0A0MTR7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RNF213ENST00000582970.6 linkc.15487G>A p.Val5163Ile missense_variant Exon 68 of 68 1 NM_001256071.3 ENSP00000464087.1 A0A0A0MTR7

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000159
AC:
40
AN:
251374
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.000290
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000362
AC:
529
AN:
1461766
Hom.:
0
Cov.:
31
AF XY:
0.000371
AC XY:
270
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000750
Gnomad4 NFE exome
AF:
0.000435
Gnomad4 OTH exome
AF:
0.000580
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000328
Hom.:
0
Bravo
AF:
0.000223
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000436
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Moyamoya disease 2 Uncertain:1
Uncertain significance, no assertion criteria providedresearchDepartment of Internal Medicine, University of Texas Health Science Center at HoustonSep 08, 2014- -
RNF213-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 28, 2023The RNF213 c.15487G>A variant is predicted to result in the amino acid substitution p.Val5163Ile. This variant was reported in an individual with Moyamoya disease (Cecchi et al. 2014. PubMed ID: 25278557). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78367161-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
13
DANN
Benign
0.77
DEOGEN2
Benign
0.013
T;T
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.29
N
LIST_S2
Benign
0.57
T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.042
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.38
N;.
REVEL
Benign
0.040
Sift
Benign
0.55
T;.
Sift4G
Benign
0.53
T;T
Vest4
0.063
MVP
0.42
MPC
0.31
ClinPred
0.029
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs201733659; hg19: chr17-78367161; API