NM_001177519.3:c.684C>T

Variant names:

• chr6-31412017-C-T
• rs1051797
• NM_001177519.3:c.684C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001177519.3(MICA):​c.684C>T​(p.Ser228Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,604,280 control chromosomes in the GnomAD database, including 73,757 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S228S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.35 (10062 hom., cov: 31)
  • Exomes 𝑓: 0.29 (63695 hom.)
• Consequence: MICA NM_001177519.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.49
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP7: Synonymous conserved (PhyloP=-2.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICA	NM_001177519.3	MANE Select	c.684C>T	p.Ser228Ser	synonymous	Exon 4 of 6	NP_001170990.1	Q96QC4
	MICA	NM_001289152.2		c.393C>T	p.Ser131Ser	synonymous	Exon 4 of 6	NP_001276081.1	A0A024RCL3
	MICA	NM_001289153.2		c.393C>T	p.Ser131Ser	synonymous	Exon 4 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.684C>T	p.Ser228Ser	synonymous	Exon 4 of 6	ENSP00000413079.1	Q96QC4
	MICA	ENST00000892120.1		c.429C>T	p.Ser143Ser	synonymous	Exon 3 of 5	ENSP00000562179.1
	MICA	ENST00000616296.4	TSL:5	c.393C>T	p.Ser131Ser	synonymous	Exon 4 of 6	ENSP00000482382.1	A0A024RCL3

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53349 AN: 151546 Hom.: 10043 Cov.: 31

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.354

GnomAD2 exomes AF: 0.310 AC: 70761 AN: 228332 AF XY: 0.301

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.285 AC: 414719 AN: 1452616 Hom.: 63695 Cov.: 51 AF XY: 0.286 AC XY: 206343 AN XY: 722110

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

African (AFR) AF: 0.456 AC: 15151 AN: 33238

American (AMR) AF: 0.447 AC: 19419 AN: 43474

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 11622 AN: 25552

East Asian (EAS) AF: 0.305 AC: 12072 AN: 39600

South Asian (SAS) AF: 0.299 AC: 25412 AN: 85066

European-Finnish (FIN) AF: 0.348 AC: 18394 AN: 52844

Middle Eastern (MID) AF: 0.294 AC: 1666 AN: 5668

European-Non Finnish (NFE) AF: 0.264 AC: 292382 AN: 1107204

Other (OTH) AF: 0.310 AC: 18601 AN: 59970

⚠️ 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.

GnomAD4 genome AF: 0.352 AC: 53414 AN: 151664 Hom.: 10062 Cov.: 31 AF XY: 0.356 AC XY: 26391 AN XY: 74138

African (AFR) AF: 0.446 AC: 18388 AN: 41244

American (AMR) AF: 0.392 AC: 5961 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1607 AN: 3454

East Asian (EAS) AF: 0.317 AC: 1626 AN: 5132

South Asian (SAS) AF: 0.306 AC: 1473 AN: 4810

European-Finnish (FIN) AF: 0.371 AC: 3918 AN: 10570

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19180 AN: 67940

Other (OTH) AF: 0.357 AC: 751 AN: 2102

Alfa AF: 0.311 Hom.: 2176

Bravo AF: 0.358

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.43
DANN	Benign	0.79
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1051797; hg19: chr6-31379794; COSMIC: COSV69826478;