6-31412040-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001177519.3(MICA):c.707T>C(p.Ile236Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,601,904 control chromosomes in the GnomAD database, including 177,143 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.54 ( 23270 hom., cov: 31)

Exomes 𝑓: 0.45 ( 153873 hom. )

Consequence

MICA
NM_001177519.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.827

Publications

27 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.5553937E-6).

BP6

Variant 6-31412040-T-C is Benign according to our data. Variant chr6-31412040-T-C is described in ClinVar as Benign. ClinVar VariationId is 403084.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

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
MICA	NM_001177519.3	MANE Select	c.707T>C	p.Ile236Thr	missense	Exon 4 of 6	NP_001170990.1
MICA	NM_001289152.2		c.416T>C	p.Ile139Thr	missense	Exon 4 of 6	NP_001276081.1
MICA	NM_001289153.2		c.416T>C	p.Ile139Thr	missense	Exon 4 of 6	NP_001276082.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MICA	ENST00000449934.7	TSL:1 MANE Select	c.707T>C	p.Ile236Thr	missense	Exon 4 of 6	ENSP00000413079.1
MICA	ENST00000892120.1		c.452T>C	p.Ile151Thr	missense	Exon 3 of 5	ENSP00000562179.1
MICA	ENST00000616296.4	TSL:5	c.416T>C	p.Ile139Thr	missense	Exon 4 of 6	ENSP00000482382.1

Frequencies

GnomAD3 genomes

AF:

0.538

AC:

81544

AN:

151448

Hom.:

23229

Cov.:

show subpopulations

Gnomad AFR

AF:

0.692

Gnomad AMI

AF:

0.512

Gnomad AMR

AF:

0.609

Gnomad ASJ

AF:

0.678

Gnomad EAS

AF:

0.438

Gnomad SAS

AF:

0.583

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.672

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.614

GnomAD2 exomes

AF:

0.492

AC:

108599

AN:

220848

AF XY:

0.492

show subpopulations

Gnomad AFR exome

AF:

0.695

Gnomad AMR exome

AF:

0.604

Gnomad ASJ exome

AF:

0.693

Gnomad EAS exome

AF:

0.422

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.419

Gnomad OTH exome

AF:

0.525

GnomAD4 exome

AF:

0.448

AC:

649164

AN:

1450338

Hom.:

153873

Cov.:

AF XY:

0.452

AC XY:

325969

AN XY:

720744

show subpopulations

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

African (AFR)

AF:

0.712

AC:

23654

AN:

33234

American (AMR)

AF:

0.625

AC:

26975

AN:

43158

Ashkenazi Jewish (ASJ)

AF:

0.675

AC:

17251

AN:

25554

East Asian (EAS)

AF:

0.507

AC:

20086

AN:

39588

South Asian (SAS)

AF:

0.579

AC:

49065

AN:

84760

European-Finnish (FIN)

AF:

0.429

AC:

22625

AN:

52722

Middle Eastern (MID)

AF:

0.690

AC:

3938

AN:

5706

European-Non Finnish (NFE)

AF:

0.413

AC:

456546

AN:

1105680

Other (OTH)

AF:

0.484

AC:

29024

AN:

59936

⚠️ 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: 0.395

Heterozygous variant carriers

16930

33860

50790

67720

84650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14082

28164

42246

56328

70410

<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:

0.539

AC:

81636

AN:

151566

Hom.:

23270

Cov.:

AF XY:

0.542

AC XY:

40160

AN XY:

74108

show subpopulations

African (AFR)

AF:

0.692

AC:

28538

AN:

41232

American (AMR)

AF:

0.610

AC:

9256

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

2347

AN:

3464

East Asian (EAS)

AF:

0.439

AC:

2247

AN:

5120

South Asian (SAS)

AF:

0.584

AC:

2805

AN:

4806

European-Finnish (FIN)

AF:

0.450

AC:

4756

AN:

10564

Middle Eastern (MID)

AF:

0.664

AC:

194

AN:

292

European-Non Finnish (NFE)

AF:

0.438

AC:

29738

AN:

67890

Other (OTH)

AF:

0.613

AC:

1291

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1847

3694

5542

7389

9236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.417

Hom.:

2152

Bravo

AF:

0.558

ExAC

AF:

0.490

AC:

59138

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.1

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.0030

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00035

MetaRNN

Benign

0.0000036

MetaSVM

Benign

-0.95

PhyloP100

-0.83

PrimateAI

Benign

0.33

PROVEAN

Benign

2.4

REVEL

Benign

0.033

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.034

MPC

0.13

ClinPred

0.0015

GERP RS

-2.4

gMVP

0.076

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over