6-29944596-T-G

Position:

• chr6-29944596-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002116.8(HLA-A):​c.992T>G​(p.Met331Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,045,166 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 13)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.280

Genes affected

HLA-A (HGNC:4931): (major histocompatibility complex, class I, A) HLA-A belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen so that they can be recognized by cytotoxic T cells. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. More than 6000 HLA-A alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]

LOC124901298 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046061873).
• BS2: High AC in GnomAd4 at 129 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-A	NM_002116.8	c.992T>G	p.Met331Arg	missense_variant	5/8	ENST00000376809.10
LOC124901298	XR_007059541.1	n.813+185A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000376809.10	c.992T>G	p.Met331Arg	missense_variant	5/8		NM_002116.8	P3

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 127 AN: 82066 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00287

Gnomad ASJ AF: 0.00336

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00120

Gnomad FIN AF: 0.000502

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.00144 AC: 1391 AN: 963064 Hom.: 3 Cov.: 23 AF XY: 0.00161 AC XY: 776 AN XY: 482426

Gnomad4 AFR exome AF: 0.00291

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.00166

Gnomad4 EAS exome AF: 0.00550

Gnomad4 SAS exome AF: 0.00505

Gnomad4 FIN exome AF: 0.000478

Gnomad4 NFE exome AF: 0.000954

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00157 AC: 129 AN: 82102 Hom.: 0 Cov.: 13 AF XY: 0.00136 AC XY: 54 AN XY: 39640

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00286

Gnomad4 ASJ AF: 0.00336

Gnomad4 EAS AF: 0.00464

Gnomad4 SAS AF: 0.00161

Gnomad4 FIN AF: 0.000502

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.0161 Hom.: 14

ExAC AF: 0.0369 AC: 4452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Benign	0.083	T;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.51	.;T;T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.18
MPC		1.2
ClinPred		0.011	T
GERP RS		-0.060
Varity_R		0.15
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1137110; hg19: chr6-29912373; COSMIC: COSV65136827; COSMIC: COSV65136827;