chr6-31412063-G-C

Position:

• chr6-31412063-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001177519.3(MICA):​c.730G>C​(p.Val244Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,032 control chromosomes in the GnomAD database, including 700 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (68 hom., cov: 32)
  • Exomes 𝑓: 0.014 (632 hom.)
• Consequence: MICA NM_001177519.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.295

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=0.0029048324).
• BP6: Variant 6-31412063-G-C is Benign according to our data. Variant chr6-31412063-G-C is described in ClinVar as [Benign]. Clinvar id is 218532.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MICA	NM_001177519.3	c.730G>C	p.Val244Leu	missense_variant	4/6	ENST00000449934.7	NP_001170990.1
MICA	NM_001289152.2	c.439G>C	p.Val147Leu	missense_variant	4/6		NP_001276081.1
MICA	NM_001289153.2	c.439G>C	p.Val147Leu	missense_variant	4/6		NP_001276082.1
MICA	NM_001289154.2	c.316G>C	p.Val106Leu	missense_variant	4/6		NP_001276083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MICA	ENST00000449934.7	c.730G>C	p.Val244Leu	missense_variant	4/6	1	NM_001177519.3	ENSP00000413079.1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2233 AN: 151848 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.000968

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0929

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0326

GnomAD3 exomes AF: 0.0213 AC: 5266 AN: 246816 Hom.: 240 AF XY: 0.0230 AC XY: 3080 AN XY: 134032

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.000560

Gnomad SAS exome AF: 0.0192

Gnomad FIN exome AF: 0.00311

Gnomad NFE exome AF: 0.0209

Gnomad OTH exome AF: 0.0312

GnomAD4 exome AF: 0.0144 AC: 21030 AN: 1461066 Hom.: 632 Cov.: 85 AF XY: 0.0155 AC XY: 11290 AN XY: 726808

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.0217

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.00360

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.0253

GnomAD4 genome AF: 0.0147 AC: 2229 AN: 151966 Hom.: 68 Cov.: 32 AF XY: 0.0149 AC XY: 1106 AN XY: 74292

Gnomad4 AFR AF: 0.00196

Gnomad4 AMR AF: 0.0257

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.000970

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0241 Hom.: 40

Bravo AF: 0.0166

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.0245 AC: 78

ExAC AF: 0.0202 AC: 2438

Asia WGS AF: 0.00751 AC: 27 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Apr 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Benign	0.021	.;.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	.;N;N
REVEL	Benign	0.057
Sift	Benign	0.15	.;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.036	.;B;.
Vest4		0.052
MutPred		0.33		.;Loss of MoRF binding (P = 0.1371);.;
MPC		0.10
ClinPred		0.0041	T
GERP RS		-1.0
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs41540613; hg19: chr6-31379840; COSMIC: COSV69826549;