NM_001177519.3:c.86G>C

Variant names:

• chr6-31410558-G-C
• rs9380254
• NM_001177519.3:c.86G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001177519.3(MICA):​c.86G>C​(p.Arg29Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,612,746 control chromosomes in the GnomAD database, including 4,897 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.054 (401 hom., cov: 32)
  • Exomes 𝑓: 0.066 (4496 hom.)
• Consequence: MICA NM_001177519.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.22
• Publications: 31 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=0.011380553).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICA	NM_001177519.3	c.86G>C	p.Arg29Pro	missense_variant	Exon 2 of 6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.-206G>C		5_prime_UTR_variant	Exon 2 of 6		NP_001276081.1
MICA	NM_001289153.2	c.-206G>C		5_prime_UTR_variant	Exon 2 of 6		NP_001276082.1
MICA	NM_001289154.2	c.-157G>C		5_prime_UTR_variant	Exon 2 of 6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.86G>C	p.Arg29Pro	missense_variant	Exon 2 of 6	1	NM_001177519.3	ENSP00000413079.1

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 8243 AN: 151874 Hom.: 401 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0586

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.0390

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0427

GnomAD2 exomes AF: 0.0783 AC: 19247 AN: 245716 AF XY: 0.0736

Gnomad AFR exome AF: 0.00948

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.00401

Gnomad EAS exome AF: 0.194

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0712

Gnomad OTH exome AF: 0.0696

GnomAD4 exome AF: 0.0660 AC: 96458 AN: 1460754 Hom.: 4496 Cov.: 35 AF XY: 0.0643 AC XY: 46730 AN XY: 726714

African (AFR) AF: 0.00751 AC: 251 AN: 33436

American (AMR) AF: 0.0988 AC: 4388 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 124 AN: 26126

East Asian (EAS) AF: 0.167 AC: 6641 AN: 39668

South Asian (SAS) AF: 0.0310 AC: 2673 AN: 86226

European-Finnish (FIN) AF: 0.132 AC: 6973 AN: 52992

Middle Eastern (MID) AF: 0.00614 AC: 35 AN: 5702

European-Non Finnish (NFE) AF: 0.0648 AC: 72075 AN: 1111826

Other (OTH) AF: 0.0547 AC: 3298 AN: 60346

GnomAD4 genome AF: 0.0542 AC: 8237 AN: 151992 Hom.: 401 Cov.: 32 AF XY: 0.0571 AC XY: 4242 AN XY: 74302

African (AFR) AF: 0.0103 AC: 427 AN: 41396

American (AMR) AF: 0.0585 AC: 890 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.190 AC: 979 AN: 5154

South Asian (SAS) AF: 0.0386 AC: 186 AN: 4818

European-Finnish (FIN) AF: 0.122 AC: 1296 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0639 AC: 4348 AN: 68022

Other (OTH) AF: 0.0423 AC: 89 AN: 2106

Alfa AF: 0.0321 Hom.: 40

Bravo AF: 0.0506

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0618 AC: 238

ESP6500AA AF: 0.0147 AC: 20

ESP6500EA AF: 0.0485 AC: 152

ExAC AF: 0.0777 AC: 9372

Asia WGS AF: 0.0600 AC: 208 AN: 3476

EpiCase AF: 0.0570

EpiControl AF: 0.0535

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0033	N
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.96	T
PhyloP100		-3.2
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Benign	0.084
Sift	Benign	0.047	D;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;.
Vest4		0.088
MPC		0.59
ClinPred		0.088	T
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.73
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs9380254; hg19: chr6-31378335; COSMIC: COSV69827193;