chr6-32581624-T-C

Variant names:

• chr6-32581624-T-C
• rs701831
• NM_002124.4:c.585A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002124.4(HLA-DRB1):​c.585A>G​(p.Arg195Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,014,598 control chromosomes in the GnomAD database, including 211,385 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 0.53 (8149 hom., cov: 7)
  • Exomes 𝑓: 0.64 (203236 hom.)
• Consequence: HLA-DRB1 NM_002124.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.465
• Publications: 20 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=0.465 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.585A>G	p.Arg195Arg	synonymous_variant	Exon 3 of 6	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.585A>G	p.Arg195Arg	synonymous_variant	Exon 3 of 6	6	NM_002124.4	ENSP00000353099.5

Frequencies

GnomAD3 genomes AF: 0.526 AC: 23223 AN: 44154 Hom.: 8134 Cov.: 7

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.750

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.839 AC: 189111 AN: 225358 AF XY: 0.836

Gnomad AFR exome AF: 0.847

Gnomad AMR exome AF: 0.883

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.833

Gnomad FIN exome AF: 0.861

Gnomad NFE exome AF: 0.830

Gnomad OTH exome AF: 0.844

GnomAD4 exome AF: 0.642 AC: 623412 AN: 970378 Hom.: 203236 Cov.: 22 AF XY: 0.642 AC XY: 313616 AN XY: 488302

African (AFR) AF: 0.664 AC: 13864 AN: 20886

American (AMR) AF: 0.659 AC: 23945 AN: 36308

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 14279 AN: 19154

East Asian (EAS) AF: 0.588 AC: 16919 AN: 28776

South Asian (SAS) AF: 0.600 AC: 35872 AN: 59772

European-Finnish (FIN) AF: 0.679 AC: 26928 AN: 39672

Middle Eastern (MID) AF: 0.671 AC: 2577 AN: 3838

European-Non Finnish (NFE) AF: 0.642 AC: 463278 AN: 722078

Other (OTH) AF: 0.645 AC: 25750 AN: 39894

GnomAD4 genome AF: 0.526 AC: 23263 AN: 44220 Hom.: 8149 Cov.: 7 AF XY: 0.517 AC XY: 10930 AN XY: 21158

African (AFR) AF: 0.472 AC: 5132 AN: 10874

American (AMR) AF: 0.562 AC: 2156 AN: 3838

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 666 AN: 970

East Asian (EAS) AF: 0.497 AC: 898 AN: 1808

South Asian (SAS) AF: 0.344 AC: 483 AN: 1406

European-Finnish (FIN) AF: 0.495 AC: 1285 AN: 2596

Middle Eastern (MID) AF: 0.563 AC: 36 AN: 64

European-Non Finnish (NFE) AF: 0.554 AC: 12075 AN: 21804

Other (OTH) AF: 0.544 AC: 298 AN: 548

Alfa AF: 0.445 Hom.: 4143

Asia WGS AF: 0.621 AC: 2160 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.63
PhyloP100		0.47
Mutation Taster		=71/29	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: rs701831; hg19: chr6-32549401;