6-32584279-AC-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002124.4(HLA-DRB1):c.199del(p.Val67CysfsTer13) 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 0.011 (13 hom., cov: 20)
  • Exomes 𝑓: 0.014 (713 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.30

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 6-32584279-AC-A is Benign according to our data. Variant chr6-32584279-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 2499004.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0109 (1262/115588) while in subpopulation EAS AF= 0.0318 (121/3808). AF 95% confidence interval is 0.0272. There are 13 homozygotes in gnomad4. There are 622 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.199del	p.Val67CysfsTer13	frameshift_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.199del	p.Val67CysfsTer13	frameshift_variant	2/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1257 AN: 115468 Hom.: 13 Cov.: 20

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00506

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.0320

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00394

Gnomad NFE AF: 0.00627

Gnomad OTH AF: 0.0109

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0142 AC: 17725 AN: 1252026 Hom.: 713 Cov.: 35 AF XY: 0.0135 AC XY: 8490 AN XY: 626704

Gnomad4 AFR exome AF: 0.0288

Gnomad4 AMR exome AF: 0.00404

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.0362

Gnomad4 SAS exome AF: 0.00735

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0109 AC: 1262 AN: 115588 Hom.: 13 Cov.: 20 AF XY: 0.0111 AC XY: 622 AN XY: 55838

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.00505

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.0318

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.00627

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00571 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

HLA-DRB1: BS1 -

Computational scores

Source: dbNSFP v4.3

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: rs200676666; hg19: chr6-32552056;