chr6-31356248-G-GTC

Variant names:

• chr6-31356248-G-GTC
• rs200488894
• NM_005514.8:c.537_538insGA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005514.8(HLA-B):​c.537_538insGA​(p.Arg180AspfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,134,496 control chromosomes in the GnomAD database, including 12,045 homozygotes. Variant has been reported in ClinVar as Benign (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.035 (118 hom., cov: 6)
  • Exomes 𝑓: 0.10 (11927 hom.)
• Consequence: HLA-B NM_005514.8 frameshift
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -4.48

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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 6-31356248-G-GTC is Benign according to our data. Variant chr6-31356248-G-GTC is described in ClinVar as [Benign]. Clinvar id is 3059849.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.537_538insGA	p.Arg180AspfsTer35	frameshift_variant	Exon 3 of 8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.537_538insGA	p.Arg180AspfsTer35	frameshift_variant	Exon 3 of 8	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.0353 AC: 1441 AN: 40814 Hom.: 118 Cov.: 6

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.00159

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0326

GnomAD2 exomes AF: 0.138 AC: 29726 AN: 214864 AF XY: 0.142

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.0803

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.103 AC: 112564 AN: 1093664 Hom.: 11927 Cov.: 29 AF XY: 0.103 AC XY: 56170 AN XY: 545360

Gnomad4 AFR exome AF: 0.0924 AC: 2495 AN: 27002

Gnomad4 AMR exome AF: 0.0558 AC: 1915 AN: 34310

Gnomad4 ASJ exome AF: 0.0864 AC: 1553 AN: 17966

Gnomad4 EAS exome AF: 0.00429 AC: 136 AN: 31674

Gnomad4 SAS exome AF: 0.0864 AC: 6253 AN: 72334

Gnomad4 FIN exome AF: 0.0699 AC: 2415 AN: 34572

Gnomad4 NFE exome AF: 0.112 AC: 92742 AN: 828322

Gnomad4 Remaining exome AF: 0.108 AC: 4771 AN: 44222

GnomAD4 genome AF: 0.0353 AC: 1440 AN: 40832 Hom.: 118 Cov.: 6 AF XY: 0.0318 AC XY: 619 AN XY: 19470

Gnomad4 AFR AF: 0.0372 AC: 0.0371807 AN: 0.0371807

Gnomad4 AMR AF: 0.0210 AC: 0.021041 AN: 0.021041

Gnomad4 ASJ AF: 0.0404 AC: 0.0404255 AN: 0.0404255

Gnomad4 EAS AF: 0.00160 AC: 0.00159744 AN: 0.00159744

Gnomad4 SAS AF: 0.0285 AC: 0.0285205 AN: 0.0285205

Gnomad4 FIN AF: 0.0128 AC: 0.0127869 AN: 0.0127869

Gnomad4 NFE AF: 0.0433 AC: 0.0433453 AN: 0.0433453

Gnomad4 OTH AF: 0.0321 AC: 0.0320513 AN: 0.0320513

Alfa AF: 0.227 Hom.: 234

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HLA-B-related disorder Benign:1

Dec 17, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=192/8	polymorphism (auto)

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200488894; hg19: chr6-31324025;