6-31412195-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001177519.3(MICA):c.862G>A(p.Gly288Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,611,518 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: MICA NM_001177519.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.400

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07299787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICA	NM_001177519.3	c.862G>A	p.Gly288Arg	missense_variant	4/6	ENST00000449934.7
MICA	NM_001289152.2	c.571G>A	p.Gly191Arg	missense_variant	4/6
MICA	NM_001289153.2	c.571G>A	p.Gly191Arg	missense_variant	4/6
MICA	NM_001289154.2	c.448G>A	p.Gly150Arg	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICA	ENST00000449934.7	c.862G>A	p.Gly288Arg	missense_variant	4/6	1	NM_001177519.3	P1
MICA	ENST00000616296.4	c.571G>A	p.Gly191Arg	missense_variant	4/6	5
MICA	ENST00000421350.1	c.535G>A	p.Gly179Arg	missense_variant	3/5	5
MICA	ENST00000674069.1	c.448G>A	p.Gly150Arg	missense_variant	4/6

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151666 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000568 AC: 14 AN: 246308 Hom.: 0 AF XY: 0.0000449 AC XY: 6 AN XY: 133684

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000391

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1459852 Hom.: 1 Cov.: 67 AF XY: 0.0000840 AC XY: 61 AN XY: 726162

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151666 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74078

Gnomad4 AFR AF: 0.000219

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000850 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.0000744 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.862G>A (p.G288R) alteration is located in exon 4 (coding exon 4) of the MICA gene. This alteration results from a G to A substitution at nucleotide position 862, causing the glycine (G) at amino acid position 288 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	14
Dann	Benign	0.81
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0065	N
M_CAP	Benign	0.00064	T
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.96	.;D;.
Vest4		0.19
MutPred		0.74		.;Gain of solvent accessibility (P = 2e-04);.;
MVP		0.072
MPC		0.20
ClinPred		0.40	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.56

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: rs377047105; hg19: chr6-31379972; COSMIC: COSV69826491;