6-32584360-G-GA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_002124.4(HLA-DRB1):c.118_119insT(p.Pro40LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.29 (1858 hom., cov: 11)
  • Exomes 𝑓: 0.25 (26799 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -10.4

Genes affected

HLA-DRB1 (HGNC:4948): (major histocompatibility complex, class II, DR beta 1) HLA-DRB1 belongs to the HLA class II beta chain paralogs. The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa. It is encoded by 6 exons. Exon one encodes the leader peptide; exons 2 and 3 encode the two extracellular domains; exon 4 encodes the transmembrane domain; and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Hundreds of DRB1 alleles have been described and some alleles have increased frequencies associated with certain diseases or conditions. For example, DRB1*1302 has been related to acute and chronic hepatitis B virus persistence. There are multiple pseudogenes of this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 6-32584360-G-GA is Benign according to our data. Variant chr6-32584360-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 3059269.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 1856 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.118_119insT	p.Pro40LeufsTer2	frameshift_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.118_119insT	p.Pro40LeufsTer2	frameshift_variant	2/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 23427 AN: 79992 Hom.: 1856 Cov.: 11

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.384

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.316

GnomAD3 exomes AF: 0.181 AC: 13599 AN: 74940 Hom.: 5254 AF XY: 0.186 AC XY: 7790 AN XY: 41846

Gnomad AFR exome AF: 0.0955

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.465

Gnomad EAS exome AF: 0.0787

Gnomad SAS exome AF: 0.217

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.225

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.251 AC: 167169 AN: 665984 Hom.: 26799 Cov.: 11 AF XY: 0.259 AC XY: 89609 AN XY: 345748

Gnomad4 AFR exome AF: 0.358

Gnomad4 AMR exome AF: 0.474

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.348

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.274

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.293 AC: 23459 AN: 80094 Hom.: 1858 Cov.: 11 AF XY: 0.292 AC XY: 11269 AN XY: 38658

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.339

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.315

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HLA-DRB1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as likely 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs769779152; hg19: chr6-32552137;