rs1555223390

Variant names:

• chr12-112911173-C-G
• rs1555223390
• NM_016816.4:c.592C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_016816.4(OAS1):​c.592C>G​(p.Leu198Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: OAS1 NM_016816.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1 O:1
• Conservation: PhyloP100: 0.354
• Publications: 1 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)

ENSG00000257452 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-112911173-C-G is Pathogenic according to our data. Variant chr12-112911173-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548129.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17822105). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OAS1	NM_016816.4	c.592C>G	p.Leu198Val	missense_variant	Exon 3 of 6	ENST00000202917.10	NP_058132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OAS1	ENST00000202917.10	c.592C>G	p.Leu198Val	missense_variant	Exon 3 of 6	1	NM_016816.4	ENSP00000202917.5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 28

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 07, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 05, 2018

OMIM

Significance: not provided

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 07, 2022

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 198 of the OAS1 protein (p.Leu198Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pulmonary alveolar proteinosis with hypogammaglobulinemia (PMID: 29455859). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 548129). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects OAS1 function (PMID: 34145065). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.037	T;.;.;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.66	T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;.;.
PhyloP100		0.35
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.91	N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T
Polyphen		0.52	P;P;B;B;.
Vest4		0.092
MutPred		0.66		Gain of MoRF binding (P = 0.0961);Gain of MoRF binding (P = 0.0961);Gain of MoRF binding (P = 0.0961);Gain of MoRF binding (P = 0.0961);.;
MVP		0.30
MPC		0.077
ClinPred		0.43	T
GERP RS		-1.3
Varity_R		0.14
gMVP		0.22
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555223390; hg19: chr12-113348978;