12-112907040-A-G

Variant names:

• chr12-112907040-A-G
• rs746226406
• NM_016816.4:c.1A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PVS1_Supporting BS2

The NM_016816.4(OAS1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: OAS1 NM_016816.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.620
• Publications: 2 publications found

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]

OAS1 Gene-Disease associations (from GenCC):

• pulmonary alveolar proteinosis with hypogammaglobulinemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 2 codons. Genomic position: 112907043. Lost 0.003 part of the original CDS.
• BS2: High AC in GnomAdExome4 at 41 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016816.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OAS1	NM_016816.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_058132.2	P00973-1
	OAS1	NM_001032409.3		c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_001027581.1	P00973-3
	OAS1	NM_001406020.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_001392949.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OAS1	ENST00000202917.10	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000202917.5	P00973-1
	OAS1	ENST00000445409.7	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000388001.2	P00973-3
	OAS1	ENST00000540589.3	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000474083.2	S4R3A5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251384 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111988

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.2
DANN	Benign	0.68
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.62
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.17
Sift	Benign	0.074	T
Sift4G	Benign	0.12	T
Polyphen		0.30	B
Vest4		0.22
MVP		0.17
ClinPred		0.42	T
GERP RS		-2.7
PromoterAI		-0.025	Neutral
Varity_R		0.24
gMVP		0.084
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs746226406; hg19: chr12-113344845;