6-31356825-T-C

Position:

• chr6-31356825-T-C

Variant summary

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

The NM_005514.8(HLA-B):​c.206A>G​(p.Glu69Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,071,252 control chromosomes in the GnomAD database, including 753 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E69K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (22 hom., cov: 0)
  • Exomes 𝑓: 0.0038 (731 hom.)
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.91

Genes affected

HLA-B (HGNC:4932): (major histocompatibility complex, class I, B) HLA-B 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. 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, exon 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. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]

HLA-B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033741891).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.206A>G	p.Glu69Gly	missense_variant	2/8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.206A>G	p.Glu69Gly	missense_variant	2/8	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 109 AN: 37842 Hom.: 22 Cov.: 0

Gnomad AFR AF: 0.000240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000317

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000952

Gnomad OTH AF: 0.00259

GnomAD3 exomes AF: 0.00593 AC: 802 AN: 135230 Hom.: 209 AF XY: 0.00612 AC XY: 443 AN XY: 72382

Gnomad AFR exome AF: 0.000918

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.000311

Gnomad EAS exome AF: 0.0850

Gnomad SAS exome AF: 0.00231

Gnomad FIN exome AF: 0.00341

Gnomad NFE exome AF: 0.000623

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00380 AC: 3924 AN: 1033376 Hom.: 731 Cov.: 27 AF XY: 0.00398 AC XY: 2042 AN XY: 513528

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.00409

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.00528

Gnomad4 FIN exome AF: 0.000518

Gnomad4 NFE exome AF: 0.000694

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00290 AC: 110 AN: 37876 Hom.: 22 Cov.: 0 AF XY: 0.00292 AC XY: 51 AN XY: 17462

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000315

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.00206

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000952

Gnomad4 OTH AF: 0.00251

ExAC AF: 0.00428 AC: 389

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.2
DANN	Benign	0.60
DEOGEN2	Benign	0.024	T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.0018	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.94	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.15
Sift	Benign	0.12	T;.;T
Sift4G	Benign	0.077	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.12
MutPred		0.25		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;
MVP		0.055
MPC		0.28
ClinPred		0.019	T
GERP RS		-6.4
Varity_R		0.33
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41562914; hg19: chr6-31324602; COSMIC: COSV69521391; COSMIC: COSV69521391;