6-29942982-T-C

Variant names:

• chr6-29942982-T-C
• rs1071742
• NM_002116.8:c.299T>C

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.299T>C​(p.Val100Ala) 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. 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. V100E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.093 (763 hom., cov: 8)
  • Exomes 𝑓: 0.23 (50739 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.41
• Publications: 29 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006266117).

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.299T>C	p.Val100Ala	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.299T>C	p.Val100Ala	missense	Exon 2 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.299T>C	p.Val100Ala	missense	Exon 2 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.299T>C	p.Val100Ala	missense	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.0931 AC: 5719 AN: 61398 Hom.: 762 Cov.: 8

Gnomad AFR AF: 0.0575

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0705

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.0955

GnomAD2 exomes AF: 0.192 AC: 43599 AN: 227030 AF XY: 0.199

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.0521

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.207

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.230 AC: 230938 AN: 1005584 Hom.: 50739 Cov.: 22 AF XY: 0.228 AC XY: 114557 AN XY: 501542

African (AFR) AF: 0.114 AC: 3012 AN: 26344

American (AMR) AF: 0.113 AC: 3293 AN: 29206

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 5219 AN: 17914

East Asian (EAS) AF: 0.0284 AC: 623 AN: 21952

South Asian (SAS) AF: 0.194 AC: 13730 AN: 70936

European-Finnish (FIN) AF: 0.0989 AC: 3567 AN: 36050

Middle Eastern (MID) AF: 0.201 AC: 702 AN: 3500

European-Non Finnish (NFE) AF: 0.253 AC: 191436 AN: 758070

Other (OTH) AF: 0.225 AC: 9356 AN: 41612

GnomAD4 genome AF: 0.0931 AC: 5720 AN: 61460 Hom.: 763 Cov.: 8 AF XY: 0.0875 AC XY: 2625 AN XY: 29992

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

African (AFR) AF: 0.0575 AC: 1035 AN: 18000

American (AMR) AF: 0.0704 AC: 349 AN: 4954

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 163 AN: 1248

East Asian (EAS) AF: 0.0164 AC: 37 AN: 2250

South Asian (SAS) AF: 0.121 AC: 246 AN: 2030

European-Finnish (FIN) AF: 0.0378 AC: 180 AN: 4762

Middle Eastern (MID) AF: 0.111 AC: 12 AN: 108

European-Non Finnish (NFE) AF: 0.133 AC: 3581 AN: 26956

Other (OTH) AF: 0.0936 AC: 76 AN: 812

⚠️ 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: 0.147 Hom.: 333

ESP6500AA AF: 0.149 AC: 656

ESP6500EA AF: 0.267 AC: 2286

ExAC AF: 0.182 AC: 22093

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.3
DANN	Benign	0.28
DEOGEN2	Benign	0.040	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.025	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.92	T
PhyloP100		-4.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.044
Sift	Benign	0.40	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.10
ClinPred		0.0061	T
GERP RS		-6.7
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.085
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: rs1071742; hg19: chr6-29910759;