NM_002116.8:c.527A>C

Variant names:

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

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>C​(p.Glu176Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E176V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (580 hom., cov: 5)
  • Exomes 𝑓: 0.21 (19395 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=0.0015471876).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 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>C	p.Glu176Ala	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>C	p.Glu176Ala	missense	Exon 3 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.527A>C	p.Glu176Ala	missense	Exon 3 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.527A>C	p.Glu176Ala	missense	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.120 AC: 4657 AN: 38902 Hom.: 580 Cov.: 5

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.0991

GnomAD2 exomes AF: 0.196 AC: 45139 AN: 230672 AF XY: 0.205

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.0976

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.197

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.206 AC: 143974 AN: 698280 Hom.: 19395 Cov.: 11 AF XY: 0.215 AC XY: 75678 AN XY: 352574

African (AFR) AF: 0.0843 AC: 1594 AN: 18898

American (AMR) AF: 0.152 AC: 2896 AN: 19014

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 3027 AN: 12378

East Asian (EAS) AF: 0.360 AC: 5418 AN: 15054

South Asian (SAS) AF: 0.364 AC: 18462 AN: 50670

European-Finnish (FIN) AF: 0.0794 AC: 2200 AN: 27694

Middle Eastern (MID) AF: 0.195 AC: 456 AN: 2334

European-Non Finnish (NFE) AF: 0.198 AC: 103710 AN: 523082

Other (OTH) AF: 0.213 AC: 6211 AN: 29156

GnomAD4 genome AF: 0.119 AC: 4651 AN: 38930 Hom.: 580 Cov.: 5 AF XY: 0.113 AC XY: 2118 AN XY: 18760

African (AFR) AF: 0.0566 AC: 609 AN: 10768

American (AMR) AF: 0.0801 AC: 220 AN: 2748

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 123 AN: 768

East Asian (EAS) AF: 0.500 AC: 345 AN: 690

South Asian (SAS) AF: 0.241 AC: 161 AN: 668

European-Finnish (FIN) AF: 0.0450 AC: 171 AN: 3802

Middle Eastern (MID) AF: 0.150 AC: 12 AN: 80

European-Non Finnish (NFE) AF: 0.156 AC: 2916 AN: 18682

Other (OTH) AF: 0.0979 AC: 46 AN: 470

Alfa AF: 0.167 Hom.: 1761

ExAC AF: 0.180 AC: 21287

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0030
DANN	Benign	0.31
DEOGEN2	Benign	0.026	T
Eigen	Benign	-3.9
Eigen_PC	Benign	-4.0
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.0052	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.86	T
PhyloP100		-12
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.13
Sift	Benign	0.56	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.088
ClinPred		0.0032	T
GERP RS		-7.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.19
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: rs9256983; hg19: chr6-29911228; COSMIC: COSV65137155; COSMIC: COSV65137155;