rs5000803

Variant names:

• chr6-32588061-T-G
• rs5000803
• NM_002124.4:c.100+1582A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

HLA-DRB1 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.100+1582A>C		intron	N/A	NP_002115.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.100+1582A>C		intron	N/A	ENSP00000353099.5
	HLA-DRB1	ENST00000696610.1		n.100+1582A>C		intron	N/A	ENSP00000512754.1
	HLA-DRB1	ENST00000696612.1		n.163+1582A>C		intron	N/A

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

African (AFR) AF: 0.577 AC: 19942 AN: 34578

American (AMR) AF: 0.691 AC: 9185 AN: 13292

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2003 AN: 3116

East Asian (EAS) AF: 0.624 AC: 2647 AN: 4240

South Asian (SAS) AF: 0.485 AC: 1845 AN: 3808

European-Finnish (FIN) AF: 0.766 AC: 7168 AN: 9354

Middle Eastern (MID) AF: 0.553 AC: 126 AN: 228

European-Non Finnish (NFE) AF: 0.670 AC: 41692 AN: 62222

Other (OTH) AF: 0.655 AC: 1173 AN: 1790

Alfa AF: 0.643 Hom.: 2414

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.5
DANN	Benign	0.49
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5000803; hg19: chr6-32555838;