6-31412380-TGCTG-T

Position:

• chr6-31412380-TGCTG-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001177519.3(MICA):​c.953_956del​(p.Gly318AlafsTer67) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,527,462 control chromosomes in the GnomAD database, including 9,654 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.15 (946 hom., cov: 20)
  • Exomes 𝑓: 0.11 (8708 hom.)
• Consequence: MICA NM_001177519.3 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.131

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 -10 ACMG points.

• BP6: Variant 6-31412380-TGCTG-T is Benign according to our data. Variant chr6-31412380-TGCTG-T is described in ClinVar as [Benign]. Clinvar id is 403086.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MICA	NM_001177519.3	c.953_956del	p.Gly318AlafsTer67	frameshift_variant	5/6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.662_665del	p.Gly221AlafsTer67	frameshift_variant	5/6		NP_001276081.1
MICA	NM_001289153.2	c.662_665del	p.Gly221AlafsTer67	frameshift_variant	5/6		NP_001276082.1
MICA	NM_001289154.2	c.539_542del	p.Gly180AlafsTer67	frameshift_variant	5/6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.953_956del	p.Gly318AlafsTer67	frameshift_variant	5/6	1	NM_001177519.3	ENSP00000413079	P1
MICA	ENST00000421350.1	c.626_629del	p.Gly209AlafsTer67	frameshift_variant	4/5	5		ENSP00000402410
MICA	ENST00000616296.4	c.662_665del	p.Gly221AlafsTer67	frameshift_variant	5/6	5		ENSP00000482382
MICA	ENST00000674069.1	c.539_542del	p.Gly180AlafsTer67	frameshift_variant	5/6			ENSP00000501157

Frequencies

GnomAD3 genomes AF: 0.152 AC: 15660 AN: 102830 Hom.: 939 Cov.: 20

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.167

GnomAD3 exomes AF: 0.158 AC: 17598 AN: 111472 Hom.: 1176 AF XY: 0.156 AC XY: 9334 AN XY: 59832

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.231

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.106 AC: 151295 AN: 1424570 Hom.: 8708 AF XY: 0.106 AC XY: 74757 AN XY: 705794

Gnomad4 AFR exome AF: 0.0763

Gnomad4 AMR exome AF: 0.0717

Gnomad4 ASJ exome AF: 0.0818

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.0717

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.152 AC: 15683 AN: 102892 Hom.: 946 Cov.: 20 AF XY: 0.157 AC XY: 7771 AN XY: 49540

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.252

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.177

Alfa AF: 0.103 Hom.: 68

Bravo AF: 0.0981

Asia WGS AF: 0.263 AC: 571 AN: 2178

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 in ESP (all): 2994/11918=25.12% -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138201170; hg19: chr6-31380157;