Genetic Variant NM_001177519.3:c.952_953insCTGCTGCT (chr6-31412384-G-GCTGCTGCT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001177519.3(MICA):c.952_953insCTGCTGCT(p.Gly318AlafsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000062 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

MICA
NM_001177519.3 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.641

Publications

18 publications found

Variant links:

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]

MICA links:

ENSG00000288587 (HGNC:):

ENSG00000288587 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICA	NM_001177519.3 link	c.952_953insCTGCTGCT	p.Gly318AlafsTer71	frameshift_variant	Exon 5 of 6	ENST00000449934.7	NP_001170990.1	Q96QC4
MICA	NM_001289152.2 link	c.661_662insCTGCTGCT	p.Gly221AlafsTer71	frameshift_variant	Exon 5 of 6		NP_001276081.1	Q96QC4A0A024RCL3
MICA	NM_001289153.2 link	c.661_662insCTGCTGCT	p.Gly221AlafsTer71	frameshift_variant	Exon 5 of 6		NP_001276082.1	Q96QC4A0A024RCL3
MICA	NM_001289154.2 link	c.538_539insCTGCTGCT	p.Gly180AlafsTer71	frameshift_variant	Exon 5 of 6		NP_001276083.1	Q96QC4A0A0G2JJ55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7 link	c.952_953insCTGCTGCT	p.Gly318AlafsTer71	frameshift_variant	Exon 5 of 6	1	NM_001177519.3	ENSP00000413079.1		Q96QC4

Frequencies

GnomAD3 genomes

AF:

0.0000165

AC:

AN:

120858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000196

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000622

AC:

AN:

1077818

Hom.:

Cov.:

AF XY:

0.0000730

AC XY:

AN XY:

534170

show subpopulations

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

African (AFR)

AF:

0.000166

AC:

AN:

30084

American (AMR)

AF:

0.000167

AC:

AN:

29942

Ashkenazi Jewish (ASJ)

AF:

0.0000919

AC:

AN:

21768

East Asian (EAS)

AF:

0.0000426

AC:

AN:

23460

South Asian (SAS)

AF:

0.000152

AC:

AN:

65870

European-Finnish (FIN)

AF:

0.0000593

AC:

AN:

33712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4822

European-Non Finnish (NFE)

AF:

0.0000498

AC:

AN:

822506

Other (OTH)

AF:

0.0000219

AC:

AN:

45654

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.339

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000165

AC:

AN:

120858

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

58664

show subpopulations

African (AFR)

AF:

0.0000264

AC:

AN:

37860

American (AMR)

AF:

0.00

AC:

AN:

12414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3034

East Asian (EAS)

AF:

0.00

AC:

AN:

2846

South Asian (SAS)

AF:

0.00

AC:

AN:

3830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.0000196

AC:

AN:

50914

Other (OTH)

AF:

0.00

AC:

AN:

1718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.64

Mutation Taster

=192/8

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over