chr12-112908582-C-T

Position:

• chr12-112908582-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS1_Moderate PM2

The NM_016816.4(OAS1):​c.227C>T​(p.Ala76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OAS1 NM_016816.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1 O:1
• Conservation: PhyloP100: 3.46

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 Uncertain_significance. Variant got 4 ACMG points.

• PS1: Transcript NM_016816.4 (OAS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OAS1	NM_016816.4	c.227C>T	p.Ala76Val	missense_variant	2/6	ENST00000202917.10	NP_058132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OAS1	ENST00000202917.10	c.227C>T	p.Ala76Val	missense_variant	2/6	1	NM_016816.4	ENSP00000202917	P2
	ENST00000552784.1	n.445+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary alveolar proteinosis with hypogammaglobulinemia Pathogenic:1 Uncertain:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 07, 2022	- -
not provided, no assertion criteria provided	literature only	OMIM	Jul 05, 2018	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 07, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T;T;D;T;D;T
M_CAP	Benign	0.0086	T
MetaRNN	Uncertain	0.44	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L;L;L;.;.;.
MutationTaster	Benign	0.88	N;N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.14	T;T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.51
MutPred		0.65		Loss of methylation at R71 (P = 0.1473);Loss of methylation at R71 (P = 0.1473);Loss of methylation at R71 (P = 0.1473);Loss of methylation at R71 (P = 0.1473);Loss of methylation at R71 (P = 0.1473);.;
MVP		0.72
MPC		0.37
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.50
gMVP		0.12

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

Other links and lift over

dbSNP: rs1555223118; hg19: chr12-113346387;