6-31410798-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PVS1_Moderate BP6_Moderate BS2

The NM_001177519.3(MICA):c.325+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,558,474 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (35 hom.)
• Consequence: MICA NM_001177519.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21

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 Likely_benign. Variant got -4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.06356356 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 6-31410798-G-A is Benign according to our data. Variant chr6-31410798-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2656400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICA	NM_001177519.3	c.325+1G>A		splice_donor_variant		ENST00000449934.7
MICA	NM_001289152.2	c.34+1G>A		splice_donor_variant
MICA	NM_001289153.2	c.34+1G>A		splice_donor_variant
MICA	NM_001289154.2	c.83+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICA	ENST00000449934.7	c.325+1G>A		splice_donor_variant		1	NM_001177519.3	P1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 151934 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00559

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00319 AC: 529 AN: 165950 Hom.: 16 AF XY: 0.00286 AC XY: 251 AN XY: 87810

Gnomad AFR exome AF: 0.000786

Gnomad AMR exome AF: 0.00556

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000173

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.00452

GnomAD4 exome AF: 0.00258 AC: 3622 AN: 1406422 Hom.: 35 Cov.: 36 AF XY: 0.00246 AC XY: 1709 AN XY: 694480

Gnomad4 AFR exome AF: 0.000566

Gnomad4 AMR exome AF: 0.00553

Gnomad4 ASJ exome AF: 0.0162

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000219

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.00255 AC: 387 AN: 152052 Hom.: 6 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74352

Gnomad4 AFR AF: 0.000773

Gnomad4 AMR AF: 0.00564

Gnomad4 ASJ AF: 0.0211

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00270

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00316 Hom.: 5

Bravo AF: 0.00294

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00346 AC: 11

ExAC AF: 0.00172 AC: 192

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

ENSG00000288587: BS2; MICA: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Benign	0.93
Eigen	Uncertain	0.49
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.66	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.60		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs181430930; hg19: chr6-31378575; COSMIC: COSV101319891;