6-31411341-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V199A) has been classified as Uncertain significance.

• 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
• Publications: 7 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 -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 VariationId is 2656401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 2103 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICA	NM_001177519.3	MANE Select	c.595G>A	p.Val199Ile	missense	Exon 3 of 6	NP_001170990.1	Q96QC4
	MICA	NM_001289152.2		c.304G>A	p.Val102Ile	missense	Exon 3 of 6	NP_001276081.1	A0A024RCL3
	MICA	NM_001289153.2		c.304G>A	p.Val102Ile	missense	Exon 3 of 6	NP_001276082.1	A0A024RCL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICA	ENST00000449934.7	TSL:1 MANE Select	c.595G>A	p.Val199Ile	missense	Exon 3 of 6	ENSP00000413079.1	Q96QC4
	MICA	ENST00000892120.1		c.340G>A	p.Val114Ile	missense	Exon 2 of 5	ENSP00000562179.1
	MICA	ENST00000616296.4	TSL:5	c.304G>A	p.Val102Ile	missense	Exon 3 of 6	ENSP00000482382.1	A0A024RCL3

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

GnomAD2 exomes AF: 0.00376 AC: 688 AN: 183212 AF XY: 0.00416

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 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

African (AFR) AF: 0.000373 AC: 12 AN: 32190

American (AMR) AF: 0.00300 AC: 112 AN: 37302

Ashkenazi Jewish (ASJ) AF: 0.000276 AC: 7 AN: 25350

East Asian (EAS) AF: 0.000784 AC: 29 AN: 36992

South Asian (SAS) AF: 0.00897 AC: 726 AN: 80970

European-Finnish (FIN) AF: 0.00161 AC: 82 AN: 50912

Middle Eastern (MID) AF: 0.0199 AC: 114 AN: 5718

European-Non Finnish (NFE) AF: 0.00231 AC: 2522 AN: 1091164

Other (OTH) AF: 0.00310 AC: 183 AN: 59028

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

African (AFR) AF: 0.000460 AC: 19 AN: 41308

American (AMR) AF: 0.00381 AC: 58 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5146

South Asian (SAS) AF: 0.00624 AC: 30 AN: 4808

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 67998

Other (OTH) AF: 0.00522 AC: 11 AN: 2106

Alfa AF: 0.00310 Hom.: 11

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
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
MetaSVM	Benign	-0.91	T
PhyloP100		-0.37
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.015
Sift	Benign	0.077	T
Sift4G	Benign	0.22	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41549718; hg19: chr6-31379118; COSMIC: COSV107515562;