6-31411341-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001177519.3(MICA):c.595G>C(p.Val199Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000634 in 1,419,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V199I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

MICA
NM_001177519.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.370

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06508893).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177519.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MICA	NM_001177519.3	MANE Select	c.595G>C	p.Val199Leu	missense	Exon 3 of 6	NP_001170990.1	Q96QC4
MICA	NM_001289152.2		c.304G>C	p.Val102Leu	missense	Exon 3 of 6	NP_001276081.1	A0A024RCL3
MICA	NM_001289153.2		c.304G>C	p.Val102Leu	missense	Exon 3 of 6	NP_001276082.1	A0A024RCL3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MICA	ENST00000449934.7	TSL:1 MANE Select	c.595G>C	p.Val199Leu	missense	Exon 3 of 6	ENSP00000413079.1	Q96QC4
MICA	ENST00000892120.1		c.340G>C	p.Val114Leu	missense	Exon 2 of 5	ENSP00000562179.1
MICA	ENST00000616296.4	TSL:5	c.304G>C	p.Val102Leu	missense	Exon 3 of 6	ENSP00000482382.1	A0A024RCL3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000634

AC:

AN:

1419648

Hom.:

Cov.:

AF XY:

0.00000427

AC XY:

AN XY:

702316

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32190

American (AMR)

AF:

0.00

AC:

AN:

37302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25350

East Asian (EAS)

AF:

0.00

AC:

AN:

36992

South Asian (SAS)

AF:

0.00

AC:

AN:

80972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00000825

AC:

AN:

1091182

Other (OTH)

AF:

0.00

AC:

AN:

59030

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000914818), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.069

(source)

DANN

Benign

0.70

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.020

M_CAP

Benign

0.0014

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.93

PhyloP100

-0.37

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.34

REVEL

Benign

0.026

Sift

Benign

0.089

Sift4G

Benign

0.37

Polyphen

0.043

Vest4

0.098

MutPred

0.39

Loss of MoRF binding (P = 0.0929)

MVP

0.014

MPC

0.11

ClinPred

0.12

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.28

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over