6-31412040-T-C

Variant names:

• chr6-31412040-T-C
• rs1140700
• NM_001177519.3:c.707T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001177519.3(MICA):​c.707T>C​(p.Ile236Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,601,904 control chromosomes in the GnomAD database, including 177,143 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.54 (23270 hom., cov: 31)
  • Exomes 𝑓: 0.45 (153873 hom.)
• Consequence: MICA NM_001177519.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.827
• Publications: 27 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.5553937E-6).
• BP6: Variant 6-31412040-T-C is Benign according to our data. Variant chr6-31412040-T-C is described in ClinVar as Benign. ClinVar VariationId is 403084.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICA	NM_001177519.3	c.707T>C	p.Ile236Thr	missense_variant	Exon 4 of 6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.416T>C	p.Ile139Thr	missense_variant	Exon 4 of 6		NP_001276081.1
MICA	NM_001289153.2	c.416T>C	p.Ile139Thr	missense_variant	Exon 4 of 6		NP_001276082.1
MICA	NM_001289154.2	c.293T>C	p.Ile98Thr	missense_variant	Exon 4 of 6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.707T>C	p.Ile236Thr	missense_variant	Exon 4 of 6	1	NM_001177519.3	ENSP00000413079.1

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81544 AN: 151448 Hom.: 23229 Cov.: 31

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.672

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.614

GnomAD2 exomes AF: 0.492 AC: 108599 AN: 220848 AF XY: 0.492

Gnomad AFR exome AF: 0.695

Gnomad AMR exome AF: 0.604

Gnomad ASJ exome AF: 0.693

Gnomad EAS exome AF: 0.422

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.419

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.448 AC: 649164 AN: 1450338 Hom.: 153873 Cov.: 65 AF XY: 0.452 AC XY: 325969 AN XY: 720744

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.712 AC: 23654 AN: 33234

American (AMR) AF: 0.625 AC: 26975 AN: 43158

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 17251 AN: 25554

East Asian (EAS) AF: 0.507 AC: 20086 AN: 39588

South Asian (SAS) AF: 0.579 AC: 49065 AN: 84760

European-Finnish (FIN) AF: 0.429 AC: 22625 AN: 52722

Middle Eastern (MID) AF: 0.690 AC: 3938 AN: 5706

European-Non Finnish (NFE) AF: 0.413 AC: 456546 AN: 1105680

Other (OTH) AF: 0.484 AC: 29024 AN: 59936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.539 AC: 81636 AN: 151566 Hom.: 23270 Cov.: 31 AF XY: 0.542 AC XY: 40160 AN XY: 74108

African (AFR) AF: 0.692 AC: 28538 AN: 41232

American (AMR) AF: 0.610 AC: 9256 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2347 AN: 3464

East Asian (EAS) AF: 0.439 AC: 2247 AN: 5120

South Asian (SAS) AF: 0.584 AC: 2805 AN: 4806

European-Finnish (FIN) AF: 0.450 AC: 4756 AN: 10564

Middle Eastern (MID) AF: 0.664 AC: 194 AN: 292

European-Non Finnish (NFE) AF: 0.438 AC: 29738 AN: 67890

Other (OTH) AF: 0.613 AC: 1291 AN: 2106

Alfa AF: 0.417 Hom.: 2152

Bravo AF: 0.558

ExAC AF: 0.490 AC: 59138

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.1
DANN	Benign	0.41
DEOGEN2	Benign	0.0030	.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00035	N
MetaRNN	Benign	0.0000036	T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.83
PrimateAI	Benign	0.33	T
PROVEAN	Benign	2.4	.;N;N
REVEL	Benign	0.033
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.034
MPC		0.13
ClinPred		0.0015	T
GERP RS		-2.4
gMVP		0.076
Mutation Taster		=96/4	polymorphism (auto)

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: rs1140700; hg19: chr6-31379817; COSMIC: COSV69826354;