6-29943287-A-G

Variant names:

• chr6-29943287-A-G
• rs1136695
• NM_002116.8:c.363A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002116.8(HLA-A):​c.363A>G​(p.Ile121Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 (1304 hom., cov: 5)
  • Exomes 𝑓: 0.14 (27444 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.67
• Publications: 30 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.371736E-6).

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.363A>G	p.Ile121Met	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.363A>G	p.Ile121Met	missense	Exon 3 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.363A>G	p.Ile121Met	missense	Exon 3 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.363A>G	p.Ile121Met	missense	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.147 AC: 6383 AN: 43362 Hom.: 1297 Cov.: 5

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.0595

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.597 AC: 119881 AN: 200820 AF XY: 0.588

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.785

Gnomad ASJ exome AF: 0.646

Gnomad EAS exome AF: 0.645

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.527

Gnomad OTH exome AF: 0.587

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.140 AC: 88000 AN: 628324 Hom.: 27444 Cov.: 10 AF XY: 0.151 AC XY: 47963 AN XY: 316988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.176 AC: 2869 AN: 16294

American (AMR) AF: 0.363 AC: 5619 AN: 15476

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 2297 AN: 10152

East Asian (EAS) AF: 0.441 AC: 5013 AN: 11364

South Asian (SAS) AF: 0.358 AC: 15972 AN: 44654

European-Finnish (FIN) AF: 0.151 AC: 4171 AN: 27596

Middle Eastern (MID) AF: 0.173 AC: 378 AN: 2184

European-Non Finnish (NFE) AF: 0.0989 AC: 46864 AN: 473810

Other (OTH) AF: 0.180 AC: 4817 AN: 26794

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.148 AC: 6402 AN: 43388 Hom.: 1304 Cov.: 5 AF XY: 0.145 AC XY: 3036 AN XY: 20994

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.202 AC: 2502 AN: 12380

American (AMR) AF: 0.184 AC: 586 AN: 3178

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 123 AN: 780

East Asian (EAS) AF: 0.179 AC: 150 AN: 836

South Asian (SAS) AF: 0.264 AC: 270 AN: 1024

European-Finnish (FIN) AF: 0.0595 AC: 232 AN: 3902

Middle Eastern (MID) AF: 0.141 AC: 9 AN: 64

European-Non Finnish (NFE) AF: 0.119 AC: 2431 AN: 20396

Other (OTH) AF: 0.146 AC: 83 AN: 568

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.466 Hom.: 2709

ESP6500AA AF: 0.542 AC: 1609

ESP6500EA AF: 0.455 AC: 2393

ExAC AF: 0.513 AC: 58839

Asia WGS AF: 0.705 AC: 2445 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.47
DANN	Benign	0.52
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.0035	T
MetaRNN	Benign	0.0000094	T
MetaSVM	Benign	-1.0	T
PhyloP100		-4.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.032
Sift	Benign	0.28	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.084
ClinPred		0.019	T
GERP RS		-7.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.10
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: rs1136695; hg19: chr6-29911064; COSMIC: COSV65136818; COSMIC: COSV65136818;