6-29942594-C-T

Position:

• chr6-29942594-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002116.8(HLA-A):​c.41C>T​(p.Ser14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002488315).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-A	NM_002116.8	c.41C>T	p.Ser14Leu	missense_variant	1/8	ENST00000376809.10	NP_002107.3
LOC124901298	XR_007059541.1	n.813+2187G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10	c.41C>T	p.Ser14Leu	missense_variant	1/8	6	NM_002116.8	ENSP00000366005.5

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

GnomAD3 exomes AF: 0.123 AC: 27925 AN: 226232 Hom.: 911 AF XY: 0.124 AC XY: 15240 AN XY: 122752

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 SAS 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

Gnomad4 AFR exome AF: 0.0651

Gnomad4 AMR exome AF: 0.0661

Gnomad4 ASJ exome AF: 0.0447

Gnomad4 EAS exome AF: 0.0539

Gnomad4 SAS exome AF: 0.0586

Gnomad4 FIN exome AF: 0.0429

Gnomad4 NFE exome AF: 0.0259

Gnomad4 OTH exome AF: 0.0394

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

Gnomad4 AFR AF: 0.0868

Gnomad4 AMR AF: 0.0748

Gnomad4 ASJ AF: 0.0635

Gnomad4 EAS AF: 0.0674

Gnomad4 SAS AF: 0.0924

Gnomad4 FIN AF: 0.0401

Gnomad4 NFE AF: 0.0520

Gnomad4 OTH AF: 0.0709

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 v4.3

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;T;T;T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.00099	N
LIST_S2	Benign	0.25	.;T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-0.85	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N;N;N;N;.
REVEL	Benign	0.050
Sift	Benign	0.13	T;T;T;.;.
Sift4G	Benign	0.11	T;T;T;T;.
Polyphen		0.0020	B;D;B;D;.
Vest4		0.070
MPC		0.074
ClinPred		0.037	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230954; hg19: chr6-29910371; COSMIC: COSV65136854;