rs9269743

Positions:

• chr6-32580214-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002124.4(HLA-DRB1):​c.787+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (11078 hom., cov: 11)
  • Exomes 𝑓: 0.43 (96143 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0320

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.787+33C>T		intron_variant		ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.787+33C>T		intron_variant			NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 32873 AN: 71596 Hom.: 11062 Cov.: 11

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.519

GnomAD3 exomes AF: 0.560 AC: 85448 AN: 152482 Hom.: 32979 AF XY: 0.568 AC XY: 47723 AN XY: 83956

Gnomad AFR exome AF: 0.669

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.651

Gnomad EAS exome AF: 0.644

Gnomad SAS exome AF: 0.619

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.552

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.426 AC: 268140 AN: 629768 Hom.: 96143 Cov.: 10 AF XY: 0.443 AC XY: 144794 AN XY: 326488

Gnomad4 AFR exome AF: 0.597

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.579

Gnomad4 EAS exome AF: 0.498

Gnomad4 SAS exome AF: 0.602

Gnomad4 FIN exome AF: 0.476

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.448

GnomAD4 genome AF: 0.459 AC: 32913 AN: 71658 Hom.: 11078 Cov.: 11 AF XY: 0.455 AC XY: 15737 AN XY: 34574

Gnomad4 AFR AF: 0.554

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.513

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.517

Alfa AF: 0.642 Hom.: 3977

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.18

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: rs9269743; hg19: chr6-32547991; COSMIC: COSV63515473;