NM_002124.4:c.371-549T>C

Variant names:

• chr6-32582387-A-G
• rs9269841
• NM_002124.4:c.371-549T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002124.4(HLA-DRB1):​c.371-549T>C 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 0.80 (35760 hom., cov: 16)
• Consequence: HLA-DRB1 NM_002124.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BS2: High Homozygotes in GnomAd4 at 35760 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.371-549T>C		intron_variant	Intron 2 of 5	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.371-549T>C		intron_variant	Intron 2 of 5	6	NM_002124.4	ENSP00000353099.5

Frequencies

GnomAD3 genomes AF: 0.800 AC: 84253 AN: 105324 Hom.: 35733 Cov.: 16

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.838

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.876

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.840

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

GnomAD4 genome AF: 0.800 AC: 84308 AN: 105392 Hom.: 35760 Cov.: 16 AF XY: 0.793 AC XY: 40240 AN XY: 50720

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.755 AC: 18016 AN: 23878

American (AMR) AF: 0.838 AC: 8695 AN: 10382

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 2470 AN: 2716

East Asian (EAS) AF: 0.761 AC: 2781 AN: 3656

South Asian (SAS) AF: 0.671 AC: 1969 AN: 2936

European-Finnish (FIN) AF: 0.802 AC: 5852 AN: 7298

Middle Eastern (MID) AF: 0.872 AC: 143 AN: 164

European-Non Finnish (NFE) AF: 0.815 AC: 42464 AN: 52116

Other (OTH) AF: 0.831 AC: 1203 AN: 1448

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.6
DANN	Benign	0.56
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs9269841; hg19: chr6-32550164;