6-29943451-A-G

Variant names:

• chr6-29943451-A-G
• rs9256983
• NM_002116.8:c.527A>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.527A>G​(p.Glu176Gly) 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 0.11 (861 hom., cov: 5)
  • Exomes 𝑓: 0.049 (8182 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=0.0020117164).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 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>G	p.Glu176Gly	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>G	p.Glu176Gly	missense	Exon 3 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.527A>G	p.Glu176Gly	missense	Exon 3 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.527A>G	p.Glu176Gly	missense	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.105 AC: 4338 AN: 41180 Hom.: 856 Cov.: 5

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.00368

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0771

Gnomad EAS AF: 0.0975

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.00347

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.0267 AC: 6163 AN: 230672 AF XY: 0.0255

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.0323

Gnomad EAS exome AF: 0.0190

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0303

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0489 AC: 36321 AN: 743134 Hom.: 8182 Cov.: 11 AF XY: 0.0479 AC XY: 17929 AN XY: 374650

African (AFR) AF: 0.276 AC: 5326 AN: 19280

American (AMR) AF: 0.0929 AC: 1804 AN: 19418

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 1002 AN: 12936

East Asian (EAS) AF: 0.0324 AC: 491 AN: 15140

South Asian (SAS) AF: 0.0323 AC: 1710 AN: 52860

European-Finnish (FIN) AF: 0.00564 AC: 164 AN: 29080

Middle Eastern (MID) AF: 0.115 AC: 281 AN: 2444

European-Non Finnish (NFE) AF: 0.0418 AC: 23438 AN: 560882

Other (OTH) AF: 0.0677 AC: 2105 AN: 31094

GnomAD4 genome AF: 0.105 AC: 4346 AN: 41210 Hom.: 861 Cov.: 5 AF XY: 0.0979 AC XY: 1940 AN XY: 19814

African (AFR) AF: 0.263 AC: 2875 AN: 10914

American (AMR) AF: 0.114 AC: 327 AN: 2868

Ashkenazi Jewish (ASJ) AF: 0.0771 AC: 62 AN: 804

East Asian (EAS) AF: 0.0977 AC: 69 AN: 706

South Asian (SAS) AF: 0.0506 AC: 36 AN: 712

European-Finnish (FIN) AF: 0.00347 AC: 14 AN: 4036

Middle Eastern (MID) AF: 0.136 AC: 12 AN: 88

European-Non Finnish (NFE) AF: 0.0435 AC: 883 AN: 20300

Other (OTH) AF: 0.131 AC: 67 AN: 510

Alfa AF: 0.0248 Hom.: 1761

ExAC AF: 0.0261 AC: 3083

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.016
DANN	Benign	0.28
DEOGEN2	Benign	0.043	T
Eigen	Benign	-3.3
Eigen_PC	Benign	-3.6
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.0035	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.54	T
PhyloP100		-12
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.21
Sift	Uncertain	0.027	D
Sift4G	Benign	0.31	T
Polyphen		0.074	B
Vest4		0.039
MPC		0.13
ClinPred		0.022	T
GERP RS		-7.6
Varity_R		0.54
gMVP		0.21
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: COSV65139076; COSMIC: COSV65139076;