NM_002116.8:c.527A>T

Variant names:

• chr6-29943451-A-T
• rs9256983
• NM_002116.8:c.527A>T

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.527A>T​(p.Glu176Val) 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 0.11 (512 hom., cov: 5)
  • Exomes 𝑓: 0.16 (20836 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -11.6
• 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=4.81467E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 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.527A>T	p.Glu176Val	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.527A>T	p.Glu176Val	missense	Exon 3 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.527A>T	p.Glu176Val	missense	Exon 3 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.527A>T	p.Glu176Val	missense	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.105 AC: 3962 AN: 37744 Hom.: 503 Cov.: 5

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0437

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.0810

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.566 AC: 130577 AN: 230672 AF XY: 0.557

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.732

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.573

Gnomad FIN exome AF: 0.531

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.566

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.157 AC: 110037 AN: 702262 Hom.: 20836 Cov.: 11 AF XY: 0.166 AC XY: 58566 AN XY: 353780

African (AFR) AF: 0.201 AC: 3547 AN: 17642

American (AMR) AF: 0.399 AC: 7069 AN: 17730

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 3000 AN: 12154

East Asian (EAS) AF: 0.434 AC: 6152 AN: 14170

South Asian (SAS) AF: 0.345 AC: 16796 AN: 48688

European-Finnish (FIN) AF: 0.0955 AC: 2584 AN: 27056

Middle Eastern (MID) AF: 0.300 AC: 700 AN: 2330

European-Non Finnish (NFE) AF: 0.122 AC: 65078 AN: 533362

Other (OTH) AF: 0.175 AC: 5111 AN: 29130

GnomAD4 genome AF: 0.106 AC: 3985 AN: 37772 Hom.: 512 Cov.: 5 AF XY: 0.104 AC XY: 1899 AN XY: 18180

African (AFR) AF: 0.141 AC: 1411 AN: 9996

American (AMR) AF: 0.168 AC: 440 AN: 2622

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 151 AN: 742

East Asian (EAS) AF: 0.179 AC: 120 AN: 670

South Asian (SAS) AF: 0.246 AC: 165 AN: 672

European-Finnish (FIN) AF: 0.0317 AC: 118 AN: 3726

Middle Eastern (MID) AF: 0.218 AC: 17 AN: 78

European-Non Finnish (NFE) AF: 0.0810 AC: 1503 AN: 18560

Other (OTH) AF: 0.108 AC: 49 AN: 454

Alfa AF: 0.461 Hom.: 1761

ExAC AF: 0.532 AC: 62925

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0020
DANN	Benign	0.50
DEOGEN2	Benign	0.023	T
Eigen	Benign	-3.4
Eigen_PC	Benign	-3.6
FATHMM_MKL	Benign	0.00089	N
LIST_S2	Benign	0.0036	T
MetaRNN	Benign	0.0000048	T
MetaSVM	Benign	-0.52	T
PhyloP100		-12
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.032
MPC		0.097
ClinPred		0.0076	T
GERP RS		-7.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
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: rs9256983; hg19: chr6-29911228; COSMIC: COSV65136508; COSMIC: COSV65136508;