12-112978645-G-A

Position:

• chr12-112978645-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000392583.7(OAS2):​c.37G>A​(p.Ala13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,614,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: OAS2 ENST00000392583.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0140

Genes affected

OAS2 (HGNC:8087): (2'-5'-oligoadenylate synthetase 2) This gene encodes a member of the 2-5A synthetase family, essential proteins involved in the innate immune response to viral infection. The encoded protein is induced by interferons and uses adenosine triphosphate in 2'-specific nucleotidyl transfer reactions to synthesize 2',5'-oligoadenylates (2-5As). These molecules activate latent RNase L, which results in viral RNA degradation and the inhibition of viral replication. The three known members of this gene family are located in a cluster on chromosome 12. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022512108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OAS2	NM_002535.3	c.37G>A	p.Ala13Thr	missense_variant	1/10	ENST00000392583.7	NP_002526.2
OAS2	NM_016817.3	c.37G>A	p.Ala13Thr	missense_variant	1/11		NP_058197.2
OAS2	NM_001032731.2	c.37G>A	p.Ala13Thr	missense_variant	1/2		NP_001027903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OAS2	ENST00000392583.7	c.37G>A	p.Ala13Thr	missense_variant	1/10	1	NM_002535.3	ENSP00000376362	P2
	ENST00000552784.1	n.353+38754C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152178 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000294 AC: 74 AN: 251322 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135828

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000363 AC: 531 AN: 1461840 Hom.: 1 Cov.: 31 AF XY: 0.000386 AC XY: 281 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000420

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152298 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.37G>A (p.A13T) alteration is located in exon 1 (coding exon 1) of the OAS2 gene. This alteration results from a G to A substitution at nucleotide position 37, causing the alanine (A) at amino acid position 13 to be replaced by a threonine (T). 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	Benign	0.18
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.5
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;.;.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.63	T;T;T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.023	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.66	N;N;D;N;.
REVEL	Benign	0.052
Sift	Benign	0.13	T;T;D;D;.
Sift4G	Benign	0.33	T;T;T;D;T
Polyphen		0.72	P;P;.;.;.
Vest4		0.093
MVP		0.26
MPC		0.45
ClinPred		0.047	T
GERP RS		0.27
Varity_R		0.040
gMVP		0.59

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: rs146990827; hg19: chr12-113416450;