6-30490287-G-T

Position:

• chr6-30490287-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005516.6(HLA-E):​c.382G>T​(p.Gly128Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,960 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G128R) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HLA-E NM_005516.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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]

HLA-E (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-E	NM_005516.6	c.382G>T	p.Gly128Trp	missense_variant	3/8	ENST00000376630.5	NP_005507.3
HLA-E	XM_017010807.2	c.505G>T	p.Gly169Trp	missense_variant	2/7		XP_016866296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-E	ENST00000376630.5	c.382G>T	p.Gly128Trp	missense_variant	3/8	6	NM_005516.6	ENSP00000365817.4
HLA-E	ENST00000484194.1	n.648G>T		non_coding_transcript_exon_variant	2/2	6
HLA-E	ENST00000493699.1	n.532G>T		non_coding_transcript_exon_variant	2/3	6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151960 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 54

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151960 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74212

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.019	N
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.072
Sift	Benign	0.036	D
Sift4G	Uncertain	0.053	T
Vest4		0.39
MutPred		0.66		Loss of methylation at R129 (P = 0.0359);
MVP		0.22
MPC		1.8
ClinPred		0.95	D
GERP RS		0.76
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.27
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1264457; hg19: chr6-30458064;