rs1137110

Variant names:

• chr6-29944596-T-G
• rs1137110
• NM_002116.8:c.992T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 19 publications found

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]

POLR1HASP (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046061873).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002116.8. 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
	HLA-A	NM_002116.8	MANE Select	c.992T>G	p.Met331Arg	missense	Exon 5 of 8	NP_002107.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.992T>G	p.Met331Arg	missense	Exon 5 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.992T>G	p.Met331Arg	missense	Exon 5 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.992T>G	p.Met331Arg	missense	Exon 6 of 8	ENSP00000516610.1	A0A9L9PYF9

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

GnomAD2 exomes AF: 0.00266 AC: 619 AN: 232552 AF XY: 0.00272

Gnomad AFR exome AF: 0.00545

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00146

Gnomad EAS exome AF: 0.000513

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00331

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

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

African (AFR) AF: 0.00291 AC: 61 AN: 20928

American (AMR) AF: 0.00391 AC: 95 AN: 24300

Ashkenazi Jewish (ASJ) AF: 0.00166 AC: 26 AN: 15710

East Asian (EAS) AF: 0.00550 AC: 117 AN: 21284

South Asian (SAS) AF: 0.00505 AC: 313 AN: 62012

European-Finnish (FIN) AF: 0.000478 AC: 17 AN: 35572

Middle Eastern (MID) AF: 0.00213 AC: 8 AN: 3764

European-Non Finnish (NFE) AF: 0.000954 AC: 706 AN: 739662

Other (OTH) AF: 0.00121 AC: 48 AN: 39832

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

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

African (AFR) AF: 0.00157 AC: 32 AN: 20422

American (AMR) AF: 0.00286 AC: 18 AN: 6290

Ashkenazi Jewish (ASJ) AF: 0.00336 AC: 6 AN: 1784

East Asian (EAS) AF: 0.00464 AC: 12 AN: 2584

South Asian (SAS) AF: 0.00161 AC: 4 AN: 2490

European-Finnish (FIN) AF: 0.000502 AC: 3 AN: 5980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.00128 AC: 52 AN: 40768

Other (OTH) AF: 0.00190 AC: 2 AN: 1052

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0129 Hom.: 14

ExAC AF: 0.0369 AC: 4452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.28
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.18
MPC		1.2
ClinPred		0.011	T
GERP RS		-0.060
Varity_R		0.15
gMVP		0.33
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1137110; hg19: chr6-29912373; COSMIC: COSV65136827; COSMIC: COSV65136827;