rs1264457

Variant names:

• chr6-30490287-G-A
• rs1264457
• NM_005516.6:c.382G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-30490287-G-A
• chr6-30490287-G-C
• chr6-30490287-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_005516.6(HLA-E):​c.382G>A​(p.Gly128Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,612,602 control chromosomes in the GnomAD database, including 269,031 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (23420 hom., cov: 32)
  • Exomes 𝑓: 0.58 (245611 hom.)
• Consequence: HLA-E NM_005516.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 65 publications found

Genes affected

HLA-E (HGNC:4962): (major histocompatibility complex, class I, E) HLA-E 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. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one 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. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-E	NM_005516.6	c.382G>A	p.Gly128Arg	missense_variant	Exon 3 of 8	ENST00000376630.5	NP_005507.3
HLA-E	XM_017010807.2	c.505G>A	p.Gly169Arg	missense_variant	Exon 2 of 7		XP_016866296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-E	ENST00000376630.5	c.382G>A	p.Gly128Arg	missense_variant	Exon 3 of 8	6	NM_005516.6	ENSP00000365817.4
HLA-E	ENST00000484194.1	n.648G>A		non_coding_transcript_exon_variant	Exon 2 of 2	6
HLA-E	ENST00000493699.1	n.532G>A		non_coding_transcript_exon_variant	Exon 2 of 3	6

Frequencies

GnomAD3 genomes AF: 0.553 AC: 83970 AN: 151902 Hom.: 23409 Cov.: 32

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.544

GnomAD2 exomes AF: 0.539 AC: 133033 AN: 246762 AF XY: 0.541

Gnomad AFR exome AF: 0.565

Gnomad AMR exome AF: 0.548

Gnomad ASJ exome AF: 0.541

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.569

Gnomad OTH exome AF: 0.544

GnomAD4 exome AF: 0.577 AC: 843086 AN: 1460580 Hom.: 245611 Cov.: 54 AF XY: 0.576 AC XY: 418743 AN XY: 726594

African (AFR) AF: 0.575 AC: 19251 AN: 33474

American (AMR) AF: 0.549 AC: 24553 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14472 AN: 26124

East Asian (EAS) AF: 0.358 AC: 14207 AN: 39700

South Asian (SAS) AF: 0.550 AC: 47416 AN: 86256

European-Finnish (FIN) AF: 0.493 AC: 25806 AN: 52302

Middle Eastern (MID) AF: 0.599 AC: 3453 AN: 5760

European-Non Finnish (NFE) AF: 0.593 AC: 658945 AN: 1111882

Other (OTH) AF: 0.580 AC: 34983 AN: 60366

GnomAD4 genome AF: 0.553 AC: 84013 AN: 152022 Hom.: 23420 Cov.: 32 AF XY: 0.544 AC XY: 40424 AN XY: 74302

African (AFR) AF: 0.567 AC: 23511 AN: 41486

American (AMR) AF: 0.524 AC: 8013 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1877 AN: 3456

East Asian (EAS) AF: 0.370 AC: 1904 AN: 5152

South Asian (SAS) AF: 0.543 AC: 2619 AN: 4820

European-Finnish (FIN) AF: 0.484 AC: 5117 AN: 10578

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39081 AN: 67928

Other (OTH) AF: 0.537 AC: 1135 AN: 2112

Alfa AF: 0.559 Hom.: 22218

Bravo AF: 0.561

TwinsUK AF: 0.599 AC: 2221

ALSPAC AF: 0.591 AC: 2278

ESP6500AA AF: 0.560 AC: 1690

ESP6500EA AF: 0.568 AC: 3076

ExAC AF: 0.535 AC: 63685

Asia WGS AF: 0.448 AC: 1558 AN: 3478

EpiCase AF: 0.577

EpiControl AF: 0.569

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.019	N
MetaRNN	Benign	0.00011	T
MetaSVM	Benign	-1.3	T
PhyloP100		1.0
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.065
Sift	Benign	0.051	T
Sift4G	Uncertain	0.058	T
Vest4		0.21
MutPred		0.73		Loss of methylation at R129 (P = 0.0423);
MPC		0.93
ClinPred		0.034	T
GERP RS		0.76
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.24
gMVP		0.82
Mutation Taster		=67/33	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1264457; hg19: chr6-30458064; COSMIC: COSV64928040; COSMIC: COSV64928040;