rs2660

chr12-112919637-G-Achr12-112919637-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The ENST00000445409.7(OAS1):c.1189G>A(p.Gly397Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,607,450 control chromosomes in the GnomAD database, including 372,892 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43967 hom., cov: 30)
  • Exomes 𝑓: 0.67 (328925 hom.)
• Consequence: OAS1 ENST00000445409.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.747

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a lipid_moiety_binding_region S-geranylgeranyl cysteine (size 0) in uniprot entity OAS1_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=9.122781E-7).
• BP6: Variant 12-112919637-G-A is Benign according to our data. Variant chr12-112919637-G-A is described in ClinVar as [Benign]. Clinvar id is 1246789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OAS1	NM_016816.4	c.*84G>A		3_prime_UTR_variant	6/6	ENST00000202917.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OAS1	ENST00000202917.10	c.*84G>A		3_prime_UTR_variant	6/6	1	NM_016816.4	P2
	ENST00000552784.1	n.354-10959C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.750 AC: 113947 AN: 151954 Hom.: 43901 Cov.: 30

Gnomad AFR AF: 0.930

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.657

Gnomad OTH AF: 0.705

GnomAD3 exomes AF: 0.715 AC: 168981 AN: 236406 Hom.: 61483 AF XY: 0.705 AC XY: 89845 AN XY: 127530

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.827

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.786

Gnomad SAS exome AF: 0.693

Gnomad FIN exome AF: 0.737

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.669 AC: 973286 AN: 1455378 Hom.: 328925 Cov.: 67 AF XY: 0.668 AC XY: 483098 AN XY: 723296

Gnomad4 AFR exome AF: 0.941

Gnomad4 AMR exome AF: 0.819

Gnomad4 ASJ exome AF: 0.512

Gnomad4 EAS exome AF: 0.796

Gnomad4 SAS exome AF: 0.692

Gnomad4 FIN exome AF: 0.730

Gnomad4 NFE exome AF: 0.650

Gnomad4 OTH exome AF: 0.665

GnomAD4 genome AF: 0.750 AC: 114077 AN: 152072 Hom.: 43967 Cov.: 30 AF XY: 0.753 AC XY: 55945 AN XY: 74330

Gnomad4 AFR AF: 0.930

Gnomad4 AMR AF: 0.767

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.774

Gnomad4 SAS AF: 0.709

Gnomad4 FIN AF: 0.729

Gnomad4 NFE AF: 0.657

Gnomad4 OTH AF: 0.708

Alfa AF: 0.664 Hom.: 72804

Bravo AF: 0.763

TwinsUK AF: 0.645 AC: 2391

ALSPAC AF: 0.660 AC: 2545

ESP6500AA AF: 0.923 AC: 4067

ESP6500EA AF: 0.646 AC: 5555

ExAC AF: 0.709 AC: 85510

Asia WGS AF: 0.767 AC: 2666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 94% of patients studied by a panel of primary immunodeficiencies. Number of patients: 89. Only high quality variants are reported. -

OAS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

This variant is associated with the following publications: (PMID: 21638280) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.9
Dann	Benign	0.51
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	9.1e-7	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	0.25	N
REVEL	Benign	0.052
Sift	Benign	0.85	T
Polyphen		0.075	B
Vest4		0.043
MutPred		0.29		Gain of sheet (P = 0.0125);
MPC		0.075
ClinPred		0.00056	T
GERP RS		0.60
gMVP		0.088

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

Other links and lift over

dbSNP: rs2660; hg19: chr12-113357442; COSMIC: COSV52534024; COSMIC: COSV52534024;