6-31412204-A-G

Position:

• chr6-31412204-A-G

Variant summary

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

The NM_001177519.3(MICA):​c.871A>G​(p.Ser291Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,611,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MICA NM_001177519.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.26

Genes affected

MICA (HGNC:7090): (MHC class I polypeptide-related sequence A) This gene encodes the highly polymorphic major histocompatability complex class I chain-related protein A. The protein product is expressed on the cell surface, although unlike canonical class I molecules it does not seem to associate with beta-2-microglobulin. It is a ligand for the NKG2-D type II integral membrane protein receptor. The protein functions as a stress-induced antigen that is broadly recognized by intestinal epithelial gamma delta T cells. Variations in this gene have been associated with susceptibility to psoriasis 1 and psoriatic arthritis, and the shedding of MICA-related antibodies and ligands is involved in the progression from monoclonal gammopathy of undetermined significance to multiple myeloma. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ENSG00000288587 (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=0.056869835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MICA	NM_001177519.3	c.871A>G	p.Ser291Gly	missense_variant	4/6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.580A>G	p.Ser194Gly	missense_variant	4/6		NP_001276081.1
MICA	NM_001289153.2	c.580A>G	p.Ser194Gly	missense_variant	4/6		NP_001276082.1
MICA	NM_001289154.2	c.457A>G	p.Ser153Gly	missense_variant	4/6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.871A>G	p.Ser291Gly	missense_variant	4/6	1	NM_001177519.3	ENSP00000413079.1

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151620 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000325 AC: 8 AN: 246076 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000592

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1459514 Hom.: 0 Cov.: 68 AF XY: 0.00000964 AC XY: 7 AN XY: 725958

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151738 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74182

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000165 AC: 2

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

Sep 12, 2024

The c.871A>G (p.S291G) alteration is located in exon 4 (coding exon 4) of the MICA gene. This alteration results from a A to G substitution at nucleotide position 871, causing the serine (S) at amino acid position 291 to be replaced by a glycine (G). 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
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.2
DANN	Benign	0.82
DEOGEN2	Benign	0.019	.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0081	N
M_CAP	Benign	0.00057	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	.;N;N
REVEL	Benign	0.021
Sift	Benign	0.21	.;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0070	.;B;.
Vest4		0.098
MutPred		0.30		.;Loss of glycosylation at S291 (P = 0.0301);.;
MVP		0.014
MPC		0.11
ClinPred		0.024	T
GERP RS		-4.1
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs61759927; hg19: chr6-31379981;