NM_001177519.3:c.595G>A

Variant names:

• chr6-31411341-G-A
• rs41549718
• NM_001177519.3:c.595G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001177519.3(MICA):​c.595G>A​(p.Val199Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,571,492 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (30 hom.)
• Consequence: MICA NM_001177519.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.370

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042325854).
• BP6: Variant 6-31411341-G-A is Benign according to our data. Variant chr6-31411341-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2656401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00267 (3787/1419626) while in subpopulation MID AF= 0.0199 (114/5718). AF 95% confidence interval is 0.017. There are 30 homozygotes in gnomad4_exome. There are 2103 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICA	NM_001177519.3	c.595G>A	p.Val199Ile	missense_variant	Exon 3 of 6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.304G>A	p.Val102Ile	missense_variant	Exon 3 of 6		NP_001276081.1
MICA	NM_001289153.2	c.304G>A	p.Val102Ile	missense_variant	Exon 3 of 6		NP_001276082.1
MICA	NM_001289154.2	c.181G>A	p.Val61Ile	missense_variant	Exon 3 of 6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.595G>A	p.Val199Ile	missense_variant	Exon 3 of 6	1	NM_001177519.3	ENSP00000413079.1

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 364 AN: 151748 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000461

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00382

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.00603

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00376 AC: 688 AN: 183212 Hom.: 11 AF XY: 0.00416 AC XY: 407 AN XY: 97752

Gnomad AFR exome AF: 0.000297

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.000227

Gnomad EAS exome AF: 0.00151

Gnomad SAS exome AF: 0.00909

Gnomad FIN exome AF: 0.00241

Gnomad NFE exome AF: 0.00379

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00267 AC: 3787 AN: 1419626 Hom.: 30 Cov.: 35 AF XY: 0.00299 AC XY: 2103 AN XY: 702304

Gnomad4 AFR exome AF: 0.000373

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.000276

Gnomad4 EAS exome AF: 0.000784

Gnomad4 SAS exome AF: 0.00897

Gnomad4 FIN exome AF: 0.00161

Gnomad4 NFE exome AF: 0.00231

Gnomad4 OTH exome AF: 0.00310

GnomAD4 genome AF: 0.00241 AC: 366 AN: 151866 Hom.: 1 Cov.: 32 AF XY: 0.00276 AC XY: 205 AN XY: 74264

Gnomad4 AFR AF: 0.000460

Gnomad4 AMR AF: 0.00381

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.00624

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00332 Hom.: 5

Bravo AF: 0.00237

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00471 AC: 15

ExAC AF: 0.00327 AC: 387

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MICA: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.32
DANN	Benign	0.79
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00046	N
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.56	.;N
REVEL	Benign	0.015
Sift	Benign	0.077	.;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0020	.;B
Vest4		0.083
MVP		0.014
MPC		0.085
ClinPred		0.0036	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs41549718; hg19: chr6-31379118;