6-31412154-G-A

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.821G>A(p.Arg274Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,609,398 control chromosomes in the GnomAD database, including 177,281 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 (23287 hom., cov: 30)
  • Exomes 𝑓: 0.45 (153994 hom.)
• Consequence: MICA NM_001177519.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00400

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=2.3832868E-6).
• BP6: Variant 6-31412154-G-A is Benign according to our data. Variant chr6-31412154-G-A is described in ClinVar as [Benign]. Clinvar id is 403085.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICA	NM_001177519.3	c.821G>A	p.Arg274Gln	missense_variant	4/6	ENST00000449934.7
MICA	NM_001289152.2	c.530G>A	p.Arg177Gln	missense_variant	4/6
MICA	NM_001289153.2	c.530G>A	p.Arg177Gln	missense_variant	4/6
MICA	NM_001289154.2	c.407G>A	p.Arg136Gln	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICA	ENST00000449934.7	c.821G>A	p.Arg274Gln	missense_variant	4/6	1	NM_001177519.3	P1
MICA	ENST00000616296.4	c.530G>A	p.Arg177Gln	missense_variant	4/6	5
MICA	ENST00000421350.1	c.494G>A	p.Arg165Gln	missense_variant	3/5	5
MICA	ENST00000674069.1	c.407G>A	p.Arg136Gln	missense_variant	4/6

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81559 AN: 151410 Hom.: 23246 Cov.: 30

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.615

GnomAD3 exomes AF: 0.505 AC: 120503 AN: 238752 Hom.: 33347 AF XY: 0.505 AC XY: 65423 AN XY: 129524

Gnomad AFR exome AF: 0.701

Gnomad AMR exome AF: 0.614

Gnomad ASJ exome AF: 0.683

Gnomad EAS exome AF: 0.434

Gnomad SAS exome AF: 0.569

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.448 AC: 653235 AN: 1457870 Hom.: 153994 Cov.: 79 AF XY: 0.453 AC XY: 328331 AN XY: 725126

Gnomad4 AFR exome AF: 0.712

Gnomad4 AMR exome AF: 0.625

Gnomad4 ASJ exome AF: 0.673

Gnomad4 EAS exome AF: 0.508

Gnomad4 SAS exome AF: 0.578

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.413

Gnomad4 OTH exome AF: 0.484

GnomAD4 genome AF: 0.539 AC: 81651 AN: 151528 Hom.: 23287 Cov.: 30 AF XY: 0.542 AC XY: 40161 AN XY: 74056

Gnomad4 AFR AF: 0.693

Gnomad4 AMR AF: 0.609

Gnomad4 ASJ AF: 0.678

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.585

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.614

Alfa AF: 0.509 Hom.: 6162

Bravo AF: 0.558

TwinsUK AF: 0.393 AC: 1458

ALSPAC AF: 0.399 AC: 1538

ExAC AF: 0.501 AC: 60473

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	-0.76	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	2.2
Dann	Benign	0.76
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00096	N
MetaRNN	Benign	0.0000024	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.33	T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0090	.;B;.
Vest4		0.029
MPC		0.12
ClinPred		0.0032	T
GERP RS		-0.10
gMVP		0.25

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: rs1063635; hg19: chr6-31379931; COSMIC: COSV69826356;