rs1051794

Variant names:

• chr6-31411332-G-A
• rs1051794
• NM_001177519.3:c.586G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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
• Publications: 62 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MICA	NM_001177519.3	c.586G>A	p.Glu196Lys	missense_variant	Exon 3 of 6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.295G>A	p.Glu99Lys	missense_variant	Exon 3 of 6		NP_001276081.1
MICA	NM_001289153.2	c.295G>A	p.Glu99Lys	missense_variant	Exon 3 of 6		NP_001276082.1
MICA	NM_001289154.2	c.172G>A	p.Glu58Lys	missense_variant	Exon 3 of 6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.586G>A	p.Glu196Lys	missense_variant	Exon 3 of 6	1	NM_001177519.3	ENSP00000413079.1

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

GnomAD2 exomes AF: 0.342 AC: 68071 AN: 199220 AF XY: 0.333

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 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

African (AFR) AF: 0.457 AC: 14874 AN: 32542

American (AMR) AF: 0.447 AC: 17282 AN: 38656

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11685 AN: 25584

East Asian (EAS) AF: 0.303 AC: 11462 AN: 37814

South Asian (SAS) AF: 0.302 AC: 24773 AN: 82092

European-Finnish (FIN) AF: 0.350 AC: 18101 AN: 51646

Middle Eastern (MID) AF: 0.299 AC: 1712 AN: 5734

European-Non Finnish (NFE) AF: 0.265 AC: 290497 AN: 1096724

Other (OTH) AF: 0.312 AC: 18535 AN: 59424

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

African (AFR) AF: 0.446 AC: 18355 AN: 41152

American (AMR) AF: 0.392 AC: 5947 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1621 AN: 3468

East Asian (EAS) AF: 0.318 AC: 1626 AN: 5120

South Asian (SAS) AF: 0.306 AC: 1468 AN: 4796

European-Finnish (FIN) AF: 0.371 AC: 3909 AN: 10546

Middle Eastern (MID) AF: 0.379 AC: 110 AN: 290

European-Non Finnish (NFE) AF: 0.283 AC: 19195 AN: 67930

Other (OTH) AF: 0.359 AC: 757 AN: 2106

Alfa AF: 0.304 Hom.: 28851

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
AlphaMissense	Benign	0.087
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
PhyloP100		0.0020
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1051794; hg19: chr6-31379109; COSMIC: COSV69826461;