6-29943448-A-G

Variant names:

• chr6-29943448-A-G
• rs1059536
• NM_002116.8:c.524A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002116.8(HLA-A):​c.524A>G​(p.His175Arg) 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).

• Frequency:
  • Genomes: 𝑓 0.15 (1750 hom., cov: 6)
  • Exomes 𝑓: 0.14 (18639 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.596
• Publications: 43 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030749738).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

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.524A>G	p.His175Arg	missense	Exon 3 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.524A>G	p.His175Arg	missense	Exon 3 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.524A>G	p.His175Arg	missense	Exon 3 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.524A>G	p.His175Arg	missense	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.154 AC: 7179 AN: 46558 Hom.: 1739 Cov.: 6

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.0185

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0768

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.175 AC: 42267 AN: 241964 AF XY: 0.172

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.0897

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.187

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.140 AC: 106627 AN: 759260 Hom.: 18639 Cov.: 11 AF XY: 0.142 AC XY: 54262 AN XY: 383160

African (AFR) AF: 0.440 AC: 8272 AN: 18784

American (AMR) AF: 0.254 AC: 5089 AN: 20000

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 2699 AN: 12922

East Asian (EAS) AF: 0.312 AC: 4878 AN: 15648

South Asian (SAS) AF: 0.190 AC: 10268 AN: 54184

European-Finnish (FIN) AF: 0.0509 AC: 1501 AN: 29468

Middle Eastern (MID) AF: 0.209 AC: 527 AN: 2524

European-Non Finnish (NFE) AF: 0.118 AC: 67724 AN: 574194

Other (OTH) AF: 0.180 AC: 5669 AN: 31536

GnomAD4 genome AF: 0.155 AC: 7201 AN: 46580 Hom.: 1750 Cov.: 6 AF XY: 0.143 AC XY: 3229 AN XY: 22502

African (AFR) AF: 0.361 AC: 4111 AN: 11396

American (AMR) AF: 0.187 AC: 602 AN: 3214

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 127 AN: 944

East Asian (EAS) AF: 0.216 AC: 172 AN: 796

South Asian (SAS) AF: 0.148 AC: 134 AN: 908

European-Finnish (FIN) AF: 0.0206 AC: 96 AN: 4650

Middle Eastern (MID) AF: 0.186 AC: 19 AN: 102

European-Non Finnish (NFE) AF: 0.0769 AC: 1819 AN: 23666

Other (OTH) AF: 0.198 AC: 115 AN: 580

Alfa AF: 0.168 Hom.: 834

ExAC AF: 0.176 AC: 20872

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.079
DANN	Benign	0.31
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.010	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.60
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.20
Sift	Benign	0.31	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.10
ClinPred		0.0062	T
GERP RS		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.048
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1059536; hg19: chr6-29911225; COSMIC: COSV65139057; COSMIC: COSV65139057;