6-32584178-G-GCT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002124.4(HLA-DRB1):c.300_301insAG(p.Arg101SerfsTer29) 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 0.21 (1045 hom., cov: 17)
  • Exomes 𝑓: 0.25 (27706 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.09

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 6-32584178-G-GCT is Benign according to our data. Variant chr6-32584178-G-GCT is described in ClinVar as [Likely_benign]. Clinvar id is 3056296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.300_301insAG	p.Arg101SerfsTer29	frameshift_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.300_301insAG	p.Arg101SerfsTer29	frameshift_variant	2/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 9548 AN: 46288 Hom.: 1041 Cov.: 17

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0509

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.0503

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.141 AC: 16882 AN: 119968 Hom.: 5531 AF XY: 0.147 AC XY: 9787 AN XY: 66372

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.0833

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.0209

Gnomad SAS exome AF: 0.143

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.146

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.253 AC: 133515 AN: 528456 Hom.: 27706 Cov.: 27 AF XY: 0.257 AC XY: 67614 AN XY: 263528

Gnomad4 AFR exome AF: 0.332

Gnomad4 AMR exome AF: 0.222

Gnomad4 ASJ exome AF: 0.376

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.267

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.206 AC: 9562 AN: 46336 Hom.: 1045 Cov.: 17 AF XY: 0.201 AC XY: 4537 AN XY: 22624

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.0516

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.212

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs778205073; hg19: chr6-32551955;