rs1059517

chr6-29943426-A-Cchr6-29943426-A-Gchr6-29943426-A-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.502A>C(p.Lys168Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 705,834 control chromosomes in the GnomAD database, including 42,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.23 (3083 hom., cov: 5)
  • Exomes 𝑓: 0.20 (39169 hom.)
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.509

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]

LOC124901298 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.544186E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-A	NM_002116.8	c.502A>C	p.Lys168Gln	missense_variant	3/8	ENST00000376809.10
LOC124901298	XR_007059541.1	n.813+1355T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000376809.10	c.502A>C	p.Lys168Gln	missense_variant	3/8		NM_002116.8	P3

Frequencies

GnomAD3 genomes AF: 0.230 AC: 9512 AN: 41280 Hom.: 3063 Cov.: 5

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.0357

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.294

GnomAD3 exomes AF: 0.244 AC: 57574 AN: 235986 Hom.: 8163 AF XY: 0.242 AC XY: 31348 AN XY: 129318

Gnomad AFR exome AF: 0.531

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.223

Gnomad SAS exome AF: 0.267

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.199 AC: 132326 AN: 664514 Hom.: 39169 Cov.: 9 AF XY: 0.201 AC XY: 67987 AN XY: 338122

Gnomad4 AFR exome AF: 0.622

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.318

Gnomad4 EAS exome AF: 0.407

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.0631

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.231 AC: 9559 AN: 41320 Hom.: 3083 Cov.: 5 AF XY: 0.216 AC XY: 4333 AN XY: 20056

Gnomad4 AFR AF: 0.529

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.300

Alfa AF: 0.171 Hom.: 486

ExAC AF: 0.238 AC: 28200

Asia WGS AF: 0.260 AC: 901 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.019
Dann	Benign	0.39
DEOGEN2	Benign	0.034	T;T;T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.044	N
MetaRNN	Benign	0.000055	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.24	N;N;N;N;.
REVEL	Benign	0.025
Sift	Benign	1.0	T;T;T;.;.
Sift4G	Benign	0.93	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.034
MPC		0.088
ClinPred		0.0039	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.28

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: rs1059517; hg19: chr6-29911203; COSMIC: COSV65138341; COSMIC: COSV65138341;