6-31412040-T-C

Position:

• chr6-31412040-T-C

Variant summary

Our verdict is Benign. Variant got -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. 12/17 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

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 -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 id 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/exons	MANE	Protein	UniProt
MICA	NM_001177519.3	c.707T>C	p.Ile236Thr	missense_variant	4/6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.416T>C	p.Ile139Thr	missense_variant	4/6		NP_001276081.1
MICA	NM_001289153.2	c.416T>C	p.Ile139Thr	missense_variant	4/6		NP_001276082.1
MICA	NM_001289154.2	c.293T>C	p.Ile98Thr	missense_variant	4/6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.707T>C	p.Ile236Thr	missense_variant	4/6	1	NM_001177519.3	ENSP00000413079	P1
MICA	ENST00000616296.4	c.416T>C	p.Ile139Thr	missense_variant	4/6	5		ENSP00000482382
MICA	ENST00000421350.1	c.380T>C	p.Ile127Thr	missense_variant	3/5	5		ENSP00000402410
MICA	ENST00000674069.1	c.293T>C	p.Ile98Thr	missense_variant	4/6			ENSP00000501157

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

GnomAD3 exomes AF: 0.492 AC: 108599 AN: 220848 Hom.: 31398 AF XY: 0.492 AC XY: 58735 AN XY: 119498

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 SAS exome AF: 0.566

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

Gnomad4 AFR exome AF: 0.712

Gnomad4 AMR exome AF: 0.625

Gnomad4 ASJ exome AF: 0.675

Gnomad4 EAS exome AF: 0.507

Gnomad4 SAS exome AF: 0.579

Gnomad4 FIN exome AF: 0.429

Gnomad4 NFE exome AF: 0.413

Gnomad4 OTH exome AF: 0.484

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

Gnomad4 AFR AF: 0.692

Gnomad4 AMR AF: 0.610

Gnomad4 ASJ AF: 0.678

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.584

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.613

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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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
MutationTaster	Benign	1.0	P;P;P;P
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

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