rs5000803

Positions:

• chr6-32588061-T-G

Variant summary

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

The NM_002124.4(HLA-DRB1):​c.100+1582A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 133,490 control chromosomes in the GnomAD database, including 28,368 homozygotes. 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 0.65 (28368 hom., cov: 22)
• Consequence: HLA-DRB1 NM_002124.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.773

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.100+1582A>C		intron_variant		ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.100+1582A>C		intron_variant			NM_002124.4	ENSP00000353099	P1
HLA-DRB1	ENST00000696610.1	c.100+1582A>C		intron_variant, NMD_transcript_variant				ENSP00000512754
HLA-DRB1	ENST00000696612.1	n.163+1582A>C		intron_variant, non_coding_transcript_variant
HLA-DRB1	ENST00000696614.1	n.228+855A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.648 AC: 86406 AN: 133396 Hom.: 28361 Cov.: 22

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.562

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.660

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.648 AC: 86445 AN: 133490 Hom.: 28368 Cov.: 22 AF XY: 0.645 AC XY: 41738 AN XY: 64668

Gnomad4 AFR AF: 0.577

Gnomad4 AMR AF: 0.691

Gnomad4 ASJ AF: 0.643

Gnomad4 EAS AF: 0.624

Gnomad4 SAS AF: 0.485

Gnomad4 FIN AF: 0.766

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.655

Alfa AF: 0.643 Hom.: 2414

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.5
DANN	Benign	0.49

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: rs5000803; hg19: chr6-32555838;