6-29942944-G-C

Variant names:

• chr6-29942944-G-C
• rs199474424
• NM_002116.8:c.261G>C

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.261G>C​(p.Glu87Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E87E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.066 (132 hom., cov: 11)
  • Exomes 𝑓: 0.12 (16383 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.813
• Publications: 24 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]

ENSG00000227766 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017453134).

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.261G>C	p.Glu87Asp	missense	Exon 2 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.261G>C	p.Glu87Asp	missense	Exon 2 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.261G>C	p.Glu87Asp	missense	Exon 2 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.261G>C	p.Glu87Asp	missense	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 5017 AN: 76066 Hom.: 132 Cov.: 11

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00607

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.0743

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0661

GnomAD2 exomes AF: 0.154 AC: 36650 AN: 237370 AF XY: 0.154

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.142

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.122 AC: 144054 AN: 1177570 Hom.: 16383 Cov.: 30 AF XY: 0.125 AC XY: 73315 AN XY: 584450

African (AFR) AF: 0.243 AC: 6802 AN: 28042

American (AMR) AF: 0.227 AC: 7617 AN: 33624

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 4749 AN: 19904

East Asian (EAS) AF: 0.152 AC: 3488 AN: 22906

South Asian (SAS) AF: 0.207 AC: 15265 AN: 73794

European-Finnish (FIN) AF: 0.0998 AC: 3966 AN: 39748

Middle Eastern (MID) AF: 0.144 AC: 568 AN: 3938

European-Non Finnish (NFE) AF: 0.105 AC: 95278 AN: 907806

Other (OTH) AF: 0.132 AC: 6321 AN: 47808

GnomAD4 genome AF: 0.0660 AC: 5023 AN: 76118 Hom.: 132 Cov.: 11 AF XY: 0.0640 AC XY: 2369 AN XY: 37026

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

African (AFR) AF: 0.122 AC: 2483 AN: 20374

American (AMR) AF: 0.0866 AC: 546 AN: 6308

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 176 AN: 1582

East Asian (EAS) AF: 0.0425 AC: 111 AN: 2614

South Asian (SAS) AF: 0.0839 AC: 201 AN: 2396

European-Finnish (FIN) AF: 0.0179 AC: 104 AN: 5804

Middle Eastern (MID) AF: 0.0809 AC: 11 AN: 136

European-Non Finnish (NFE) AF: 0.0374 AC: 1325 AN: 35442

Other (OTH) AF: 0.0651 AC: 63 AN: 968

⚠️ 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: 0.0297 Hom.: 59

ESP6500AA AF: 0.0368 AC: 162

ESP6500EA AF: 0.00874 AC: 75

ExAC AF: 0.154 AC: 18721

Asia WGS AF: 0.196 AC: 682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.58
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.014	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.81
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.040
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.0040	B
Vest4		0.072
MutPred		0.40		Loss of helix (P = 0.0444)
MPC		0.081
ClinPred		0.036	T
GERP RS		0.50
PromoterAI		-0.012	Neutral
Varity_R		0.54
gMVP		0.23
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: rs199474424; hg19: chr6-29910721; COSMIC: COSV65139183;