6-32581624-T-C

Position:

• chr6-32581624-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 6-32581624-T-C is Benign according to our data. Variant chr6-32581624-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.585A>G	p.Arg195Arg	synonymous_variant	3/6	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.585A>G	p.Arg195Arg	synonymous_variant	3/6	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

GnomAD3 exomes AF: 0.839 AC: 189111 AN: 225358 Hom.: 81672 AF XY: 0.836 AC XY: 102888 AN XY: 123026

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 SAS exome AF: 0.782

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

Gnomad4 AFR exome AF: 0.664

Gnomad4 AMR exome AF: 0.659

Gnomad4 ASJ exome AF: 0.745

Gnomad4 EAS exome AF: 0.588

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.679

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.645

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

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.562

Gnomad4 ASJ AF: 0.687

Gnomad4 EAS AF: 0.497

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.544

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

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: rs701831; hg19: chr6-32549401;