6-32584283-A-AG

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.195_196insC(p.Ser66LeufsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,397,956 control chromosomes in the GnomAD database, including 745 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 22)
  • Exomes 𝑓: 0.014 (734 hom.)
• Consequence: HLA-DRB1 NM_002124.4 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.31

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 6-32584283-A-AG is Benign according to our data. Variant chr6-32584283-A-AG is described in ClinVar as [Benign]. Clinvar id is 2499005.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0103 (1310/127282) while in subpopulation EAS AF= 0.0306 (128/4178). AF 95% confidence interval is 0.0263. There are 11 homozygotes in gnomad4. There are 626 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.195_196insC	p.Ser66LeufsTer21	frameshift_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.195_196insC	p.Ser66LeufsTer21	frameshift_variant	2/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1304 AN: 127186 Hom.: 11 Cov.: 22

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00448

Gnomad ASJ AF: 0.0146

Gnomad EAS AF: 0.0308

Gnomad SAS AF: 0.00639

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00347

Gnomad NFE AF: 0.00620

Gnomad OTH AF: 0.0107

GnomAD3 exomes AF: 0.00000527 AC: 1 AN: 189704 Hom.: 0 AF XY: 0.00000957 AC XY: 1 AN XY: 104442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0140 AC: 17832 AN: 1270674 Hom.: 734 Cov.: 34 AF XY: 0.0135 AC XY: 8589 AN XY: 637308

Gnomad4 AFR exome AF: 0.0267

Gnomad4 AMR exome AF: 0.00433

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.0355

Gnomad4 SAS exome AF: 0.00697

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0103 AC: 1310 AN: 127282 Hom.: 11 Cov.: 22 AF XY: 0.0101 AC XY: 626 AN XY: 61774

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.00447

Gnomad4 ASJ AF: 0.0146

Gnomad4 EAS AF: 0.0306

Gnomad4 SAS AF: 0.00641

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00620

Gnomad4 OTH AF: 0.0112

Alfa AF: 0.0501 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

HLA-DRB1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1440748108; hg19: chr6-32552060; COSMIC: COSV63511460;