20-63541501-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080823.4(SRMS):​c.1066G>A​(p.Val356Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,607,930 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

SRMS
NM_080823.4 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.15
Variant links:
Genes affected
SRMS (HGNC:11298): (src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites) Enables protein tyrosine kinase activity. Involved in peptidyl-tyrosine autophosphorylation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SRMSNM_080823.4 linkc.1066G>A p.Val356Met missense_variant Exon 6 of 8 ENST00000217188.2 NP_543013.1 Q9H3Y6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SRMSENST00000217188.2 linkc.1066G>A p.Val356Met missense_variant Exon 6 of 8 1 NM_080823.4 ENSP00000217188.1 Q9H3Y6

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
34
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:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000251
AC:
6
AN:
238572
Hom.:
0
AF XY:
0.0000306
AC XY:
4
AN XY:
130618
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000166
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000933
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000124
AC:
18
AN:
1455764
Hom.:
1
Cov.:
34
AF XY:
0.0000193
AC XY:
14
AN XY:
724278
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000163
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000249
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 12, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1066G>A (p.V356M) alteration is located in exon 6 (coding exon 6) of the SRMS gene. This alteration results from a G to A substitution at nucleotide position 1066, causing the valine (V) at amino acid position 356 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
D
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Benign
0.71
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.023
T
MetaRNN
Uncertain
0.60
D
MetaSVM
Benign
-0.88
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-2.5
D
REVEL
Benign
0.24
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.41
MutPred
0.72
Gain of sheet (P = 0.1208);
MVP
0.33
MPC
0.64
ClinPred
0.77
D
GERP RS
2.9
Varity_R
0.43
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs769815109; hg19: chr20-62172854; API