6-29942985-A-G

Variant names:

• chr6-29942985-A-G
• rs2231004
• NM_002116.8:c.302A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_002116.8(HLA-A):​c.302A>G​(p.Asp101Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D101N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (102 hom., cov: 5)
  • Exomes 𝑓: 0.045 (3875 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 20 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002359569).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0285 (1474/51706) while in subpopulation NFE AF = 0.0349 (934/26754). AF 95% confidence interval is 0.0331. There are 102 homozygotes in GnomAd4. There are 701 alleles in the male GnomAd4 subpopulation. Median coverage is 5. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1474 AD gene.

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.302A>G	p.Asp101Gly	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.302A>G	p.Asp101Gly	missense	Exon 2 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.302A>G	p.Asp101Gly	missense	Exon 2 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.302A>G	p.Asp101Gly	missense	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 1471 AN: 51686 Hom.: 102 Cov.: 5

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.0443

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00624

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0119

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0219

GnomAD2 exomes AF: 0.0422 AC: 9524 AN: 225872 AF XY: 0.0432

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.0302

Gnomad ASJ exome AF: 0.0493

Gnomad EAS exome AF: 0.00511

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0539

Gnomad OTH exome AF: 0.0490

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0452 AC: 45097 AN: 998028 Hom.: 3875 Cov.: 19 AF XY: 0.0457 AC XY: 22572 AN XY: 494100

African (AFR) AF: 0.0136 AC: 308 AN: 22700

American (AMR) AF: 0.0323 AC: 797 AN: 24688

Ashkenazi Jewish (ASJ) AF: 0.0457 AC: 716 AN: 15666

East Asian (EAS) AF: 0.00381 AC: 53 AN: 13910

South Asian (SAS) AF: 0.0387 AC: 2417 AN: 62434

European-Finnish (FIN) AF: 0.0449 AC: 1623 AN: 36114

Middle Eastern (MID) AF: 0.0578 AC: 186 AN: 3218

European-Non Finnish (NFE) AF: 0.0479 AC: 37323 AN: 779950

Other (OTH) AF: 0.0425 AC: 1674 AN: 39348

GnomAD4 genome AF: 0.0285 AC: 1474 AN: 51706 Hom.: 102 Cov.: 5 AF XY: 0.0277 AC XY: 701 AN XY: 25342

African (AFR) AF: 0.0166 AC: 181 AN: 10926

American (AMR) AF: 0.0301 AC: 108 AN: 3586

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 36 AN: 976

East Asian (EAS) AF: 0.00626 AC: 11 AN: 1756

South Asian (SAS) AF: 0.0286 AC: 44 AN: 1538

European-Finnish (FIN) AF: 0.0252 AC: 127 AN: 5046

Middle Eastern (MID) AF: 0.0125 AC: 1 AN: 80

European-Non Finnish (NFE) AF: 0.0349 AC: 934 AN: 26754

Other (OTH) AF: 0.0219 AC: 14 AN: 638

Alfa AF: 0.0436 Hom.: 49

ExAC AF: 0.0417 AC: 4828

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.0
DANN	Benign	0.48
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.91	T
PhyloP100		-1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.091
Sift	Benign	0.068	T
Sift4G	Benign	0.17	T
Polyphen		0.058	B
Vest4		0.060
MPC		0.17
ClinPred		0.0074	T
GERP RS		-3.8
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.23
Mutation Taster		=99/1	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: rs2231004; hg19: chr6-29910762;