6-29942990-G-C

Variant names:

• chr6-29942990-G-C
• rs1136689
• NM_002116.8:c.307G>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.307G>C​(p.Gly103Arg) 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 (264 hom., cov: 8)
  • Exomes 𝑓: 0.14 (15368 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.67
• Publications: 19 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050683618).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 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.307G>C	p.Gly103Arg	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.307G>C	p.Gly103Arg	missense	Exon 2 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.307G>C	p.Gly103Arg	missense	Exon 2 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.307G>C	p.Gly103Arg	missense	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.146 AC: 9195 AN: 63010 Hom.: 261 Cov.: 8

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.0638

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.162 AC: 35742 AN: 221230 AF XY: 0.163

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.173

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.136 AC: 135372 AN: 993170 Hom.: 15368 Cov.: 21 AF XY: 0.139 AC XY: 68539 AN XY: 493596

African (AFR) AF: 0.147 AC: 3594 AN: 24484

American (AMR) AF: 0.228 AC: 6297 AN: 27658

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 3135 AN: 17220

East Asian (EAS) AF: 0.245 AC: 4827 AN: 19684

South Asian (SAS) AF: 0.194 AC: 12921 AN: 66620

European-Finnish (FIN) AF: 0.0905 AC: 3168 AN: 35008

Middle Eastern (MID) AF: 0.178 AC: 594 AN: 3332

European-Non Finnish (NFE) AF: 0.125 AC: 94721 AN: 758588

Other (OTH) AF: 0.151 AC: 6115 AN: 40576

GnomAD4 genome AF: 0.146 AC: 9224 AN: 63064 Hom.: 264 Cov.: 8 AF XY: 0.142 AC XY: 4354 AN XY: 30632

African (AFR) AF: 0.226 AC: 3945 AN: 17492

American (AMR) AF: 0.200 AC: 999 AN: 4988

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 250 AN: 1330

East Asian (EAS) AF: 0.157 AC: 321 AN: 2050

South Asian (SAS) AF: 0.175 AC: 347 AN: 1980

European-Finnish (FIN) AF: 0.0408 AC: 204 AN: 4998

Middle Eastern (MID) AF: 0.194 AC: 24 AN: 124

European-Non Finnish (NFE) AF: 0.103 AC: 2973 AN: 28880

Other (OTH) AF: 0.164 AC: 136 AN: 830

Alfa AF: 0.148 Hom.: 496

ExAC AF: 0.161 AC: 19482

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.2
DANN	Benign	0.29
DEOGEN2	Benign	0.020	T
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.019	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.94	T
PhyloP100		-5.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.066
Sift	Benign	0.50	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.034
MutPred		0.31		Gain of MoRF binding (P = 0.0084)
MPC		0.10
ClinPred		0.0052	T
GERP RS		-7.2
PromoterAI		0.0018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.13
Mutation Taster		=97/3	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: rs1136689; hg19: chr6-29910767; COSMIC: COSV65141826;