rs1051794

Positions:

• chr6-31411332-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001177519.3(MICA):​c.586G>A​(p.Glu196Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,581,700 control chromosomes in the GnomAD database, including 72,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.35 (10079 hom., cov: 30)
  • Exomes 𝑓: 0.29 (61959 hom.)
• Consequence: MICA NM_001177519.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.834201E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MICA	NM_001177519.3	c.586G>A	p.Glu196Lys	missense_variant	3/6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.295G>A	p.Glu99Lys	missense_variant	3/6		NP_001276081.1
MICA	NM_001289153.2	c.295G>A	p.Glu99Lys	missense_variant	3/6		NP_001276082.1
MICA	NM_001289154.2	c.172G>A	p.Glu58Lys	missense_variant	3/6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.586G>A	p.Glu196Lys	missense_variant	3/6	1	NM_001177519.3	ENSP00000413079	P1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53325 AN: 151366 Hom.: 10060 Cov.: 30

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.372

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.356

GnomAD3 exomes AF: 0.342 AC: 68071 AN: 199220 Hom.: 12685 AF XY: 0.333 AC XY: 35583 AN XY: 106896

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.454

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.344

Gnomad SAS exome AF: 0.294

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.286 AC: 408921 AN: 1430216 Hom.: 61959 Cov.: 53 AF XY: 0.286 AC XY: 202843 AN XY: 708540

Gnomad4 AFR exome AF: 0.457

Gnomad4 AMR exome AF: 0.447

Gnomad4 ASJ exome AF: 0.457

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.302

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.265

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.352 AC: 53390 AN: 151484 Hom.: 10079 Cov.: 30 AF XY: 0.356 AC XY: 26381 AN XY: 74044

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.467

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.283

Gnomad4 OTH AF: 0.359

Alfa AF: 0.304 Hom.: 13375

Bravo AF: 0.358

TwinsUK AF: 0.257 AC: 953

ALSPAC AF: 0.248 AC: 957

ESP6500AA AF: 0.419 AC: 580

ESP6500EA AF: 0.289 AC: 919

ExAC AF: 0.309 AC: 36751

Asia WGS AF: 0.367 AC: 1273 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.74
DANN	Benign	0.75
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
MetaRNN	Benign	0.00028	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	.;N
REVEL	Benign	0.033
Sift	Benign	0.83	.;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0050	.;B
Vest4		0.12
MPC		0.12
ClinPred		0.0033	T
GERP RS		-0.81
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1051794; hg19: chr6-31379109; COSMIC: COSV69826461;