6-29942594-C-T

Variant names:

• chr6-29942594-C-T
• rs2230954
• NM_002116.8:c.41C>T

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.41C>T​(p.Ser14Leu) 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 0.065 (266 hom., cov: 17)
  • Exomes 𝑓: 0.032 (2894 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.59
• Publications: 23 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=0.002488315).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	NM_002116.8	MANE Select	c.41C>T	p.Ser14Leu	missense	Exon 1 of 8	NP_002107.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.41C>T	p.Ser14Leu	missense	Exon 1 of 8	ENSP00000366005.5
	HLA-A	ENST00000706894.1		c.41C>T	p.Ser14Leu	missense	Exon 2 of 8	ENSP00000516610.1
	HLA-A	ENST00000376806.9	TSL:6	c.41C>T	p.Ser14Leu	missense	Exon 1 of 8	ENSP00000366002.5

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 6378 AN: 98204 Hom.: 265 Cov.: 17

Gnomad AFR AF: 0.0867

Gnomad AMI AF: 0.0550

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.0635

Gnomad EAS AF: 0.0666

Gnomad SAS AF: 0.0924

Gnomad FIN AF: 0.0401

Gnomad MID AF: 0.0787

Gnomad NFE AF: 0.0520

Gnomad OTH AF: 0.0707

GnomAD2 exomes AF: 0.123 AC: 27925 AN: 226232 AF XY: 0.124

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.155

Gnomad FIN exome AF: 0.0834

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.127

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0317 AC: 30255 AN: 952964 Hom.: 2894 Cov.: 30 AF XY: 0.0336 AC XY: 15944 AN XY: 474150

African (AFR) AF: 0.0651 AC: 1407 AN: 21616

American (AMR) AF: 0.0661 AC: 1329 AN: 20120

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 683 AN: 15280

East Asian (EAS) AF: 0.0539 AC: 1169 AN: 21696

South Asian (SAS) AF: 0.0586 AC: 3320 AN: 56634

European-Finnish (FIN) AF: 0.0429 AC: 1464 AN: 34104

Middle Eastern (MID) AF: 0.0421 AC: 148 AN: 3516

European-Non Finnish (NFE) AF: 0.0259 AC: 19150 AN: 739748

Other (OTH) AF: 0.0394 AC: 1585 AN: 40250

GnomAD4 genome AF: 0.0651 AC: 6391 AN: 98236 Hom.: 266 Cov.: 17 AF XY: 0.0627 AC XY: 2972 AN XY: 47382

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

African (AFR) AF: 0.0868 AC: 2330 AN: 26846

American (AMR) AF: 0.0748 AC: 643 AN: 8602

Ashkenazi Jewish (ASJ) AF: 0.0635 AC: 140 AN: 2204

East Asian (EAS) AF: 0.0674 AC: 215 AN: 3188

South Asian (SAS) AF: 0.0924 AC: 283 AN: 3062

European-Finnish (FIN) AF: 0.0401 AC: 265 AN: 6612

Middle Eastern (MID) AF: 0.0842 AC: 17 AN: 202

European-Non Finnish (NFE) AF: 0.0520 AC: 2372 AN: 45604

Other (OTH) AF: 0.0709 AC: 92 AN: 1298

⚠️ 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: 0.0651 Hom.: 78

TwinsUK AF: 0.103 AC: 383

ALSPAC AF: 0.109 AC: 420

ESP6500AA AF: 0.166 AC: 731

ESP6500EA AF: 0.106 AC: 907

ExAC AF: 0.118 AC: 14345

Asia WGS AF: 0.134 AC: 465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.9
DANN	Benign	0.93
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.00099	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.85	T
PhyloP100		-4.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.050
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.070
MPC		0.074
ClinPred		0.037	T
GERP RS		-1.4
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.11
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: rs2230954; hg19: chr6-29910371; COSMIC: COSV65136854;