NM_001177519.3:c.952_953insCTGCTGCTGCT

Variant names:

• chr6-31412384-G-GCTGCTGCTGCT
• rs41293539
• NM_001177519.3:c.952_953insCTGCTGCTGCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001177519.3(MICA):​c.952_953insCTGCTGCTGCT​(p.Gly318AlafsTer72) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.28 (4518 hom., cov: 0)
  • Exomes 𝑓: 0.20 (19456 hom.)
  • Failed GnomAD Quality Control
• Consequence: MICA NM_001177519.3 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.641
• Publications: 18 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 -10 ACMG points.

• BP6: Variant 6-31412384-G-GCTGCTGCTGCT is Benign according to our data. Variant chr6-31412384-G-GCTGCTGCTGCT is described in ClinVar as Benign. ClinVar VariationId is 403088.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICA	NM_001177519.3	c.952_953insCTGCTGCTGCT	p.Gly318AlafsTer72	frameshift_variant	Exon 5 of 6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.661_662insCTGCTGCTGCT	p.Gly221AlafsTer72	frameshift_variant	Exon 5 of 6		NP_001276081.1
MICA	NM_001289153.2	c.661_662insCTGCTGCTGCT	p.Gly221AlafsTer72	frameshift_variant	Exon 5 of 6		NP_001276082.1
MICA	NM_001289154.2	c.538_539insCTGCTGCTGCT	p.Gly180AlafsTer72	frameshift_variant	Exon 5 of 6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.952_953insCTGCTGCTGCT	p.Gly318AlafsTer72	frameshift_variant	Exon 5 of 6	1	NM_001177519.3	ENSP00000413079.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 33466 AN: 120772 Hom.: 4510 Cov.: 0

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.270

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.252

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.198 AC: 211320 AN: 1069922 Hom.: 19456 Cov.: 35 AF XY: 0.199 AC XY: 105189 AN XY: 529734

African (AFR) AF: 0.367 AC: 10945 AN: 29840

American (AMR) AF: 0.388 AC: 11343 AN: 29254

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 6263 AN: 21350

East Asian (EAS) AF: 0.255 AC: 5958 AN: 23368

South Asian (SAS) AF: 0.271 AC: 17413 AN: 64290

European-Finnish (FIN) AF: 0.308 AC: 10216 AN: 33194

Middle Eastern (MID) AF: 0.172 AC: 828 AN: 4802

European-Non Finnish (NFE) AF: 0.169 AC: 138443 AN: 818488

Other (OTH) AF: 0.219 AC: 9911 AN: 45336

GnomAD4 genome AF: 0.277 AC: 33509 AN: 120856 Hom.: 4518 Cov.: 0 AF XY: 0.285 AC XY: 16714 AN XY: 58708

African (AFR) AF: 0.360 AC: 13665 AN: 37944

American (AMR) AF: 0.328 AC: 4071 AN: 12414

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 955 AN: 3034

East Asian (EAS) AF: 0.315 AC: 895 AN: 2840

South Asian (SAS) AF: 0.286 AC: 1090 AN: 3816

European-Finnish (FIN) AF: 0.339 AC: 2439 AN: 7186

Middle Eastern (MID) AF: 0.284 AC: 67 AN: 236

European-Non Finnish (NFE) AF: 0.188 AC: 9577 AN: 50894

Other (OTH) AF: 0.252 AC: 432 AN: 1714

Alfa AF: 0.00 Hom.: 0

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: Not present in FAST (frequency). ExAC: 23.9% (9166/38406) total chromosomes -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.64
Mutation Taster		=193/7	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41293539; hg19: chr6-31380161; COSMIC: COSV69826307;