12-112907045-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016816.4(OAS1):​c.6G>A​(p.Met2Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

OAS1
NM_016816.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.695
Variant links:
Genes affected
OAS1 (HGNC:8086): (2'-5'-oligoadenylate synthetase 1) This interferon-induced gene encodes a protein that synthesizes 2',5'-oligoadenylates (2-5As). This protein plays a key role in innate cellular antiviral response, and has been implicated in other cellular processes like cell growth and apoptosis. Alternative splicing results in multiple transcript variants with different enzymatic activities. Polymorphisms in this gene have been associated with susceptibility to viral infection, including SARS-CoV-2, and diabetes mellitus, type 1. This gene is located in a cluster of related genes on chromosome 12. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08089882).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OAS1NM_016816.4 linkc.6G>A p.Met2Ile missense_variant Exon 1 of 6 ENST00000202917.10 NP_058132.2 P00973-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OAS1ENST00000202917.10 linkc.6G>A p.Met2Ile missense_variant Exon 1 of 6 1 NM_016816.4 ENSP00000202917.5 P00973-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
32
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:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251386
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461868
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000660
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Nov 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2 of the OAS1 protein (p.Met2Ile). This variant is present in population databases (rs576801406, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with OAS1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
17
DANN
Benign
0.65
DEOGEN2
Benign
0.084
T;.;.;T;.;.
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.85
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.56
T;T;T;T;T;T
M_CAP
Benign
0.0038
T
MetaRNN
Benign
0.081
T;T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.9
L;L;L;.;.;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.8
N;N;N;N;N;N
REVEL
Benign
0.091
Sift
Benign
0.11
T;T;T;T;T;D
Sift4G
Benign
0.38
T;T;T;T;T;T
Polyphen
0.083
B;B;B;.;P;.
Vest4
0.20
MutPred
0.24
Gain of catalytic residue at M2 (P = 0.0634);Gain of catalytic residue at M2 (P = 0.0634);Gain of catalytic residue at M2 (P = 0.0634);Gain of catalytic residue at M2 (P = 0.0634);Gain of catalytic residue at M2 (P = 0.0634);Gain of catalytic residue at M2 (P = 0.0634);
MVP
0.25
MPC
0.15
ClinPred
0.12
T
GERP RS
-0.71
Varity_R
0.21
gMVP
0.12

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs576801406; hg19: chr12-113344850; API