6-29943309-T-C

Position:

• chr6-29943309-T-C

Variant summary

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

The NM_002116.8(HLA-A):​c.385T>C​(p.Ser129Pro) 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 0.17 (1947 hom., cov: 6)
  • Exomes 𝑓: 0.26 (54455 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.424

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=0.0011473894).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-A	NM_002116.8	c.385T>C	p.Ser129Pro	missense_variant	3/8	ENST00000376809.10
LOC124901298	XR_007059541.1	n.813+1472A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000376809.10	c.385T>C	p.Ser129Pro	missense_variant	3/8		NM_002116.8	P3

Frequencies

GnomAD3 genomes AF: 0.171 AC: 8580 AN: 50086 Hom.: 1945 Cov.: 6

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.0635

Gnomad MID AF: 0.240

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.157

GnomAD3 exomes AF: 0.318 AC: 72655 AN: 228474 Hom.: 14458 AF XY: 0.329 AC XY: 41253 AN XY: 125212

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.360

Gnomad SAS exome AF: 0.415

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.346

Gnomad OTH exome AF: 0.311

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.258 AC: 160584 AN: 621420 Hom.: 54455 Cov.: 9 AF XY: 0.275 AC XY: 86942 AN XY: 316392

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.187

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.171 AC: 8584 AN: 50122 Hom.: 1947 Cov.: 6 AF XY: 0.163 AC XY: 3940 AN XY: 24180

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.516

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.0635

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.156

Alfa AF: 0.330 Hom.: 2820

ESP6500AA AF: 0.268 AC: 803

ESP6500EA AF: 0.348 AC: 1878

ExAC AF: 0.311 AC: 36954

Asia WGS AF: 0.313 AC: 1091 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.7
DANN	Benign	0.88
DEOGEN2	Benign	0.020	T;T;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0023	N
MetaRNN	Benign	0.0011	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	4.9	N;N;N;N;.
REVEL	Benign	0.042
Sift	Benign	1.0	T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.038
MPC		0.10
ClinPred		0.00030	T
GERP RS		-0.46
Varity_R		0.25
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1136700; hg19: chr6-29911086; COSMIC: COSV65136992; COSMIC: COSV65136992;