rs707954

Variant names:

• chr6-32581724-A-C
• rs707954
• NM_002124.4:c.485T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-32581724-A-C
• chr6-32581724-A-G
• chr6-32581724-A-T

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.485T>G​(p.Leu162Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,221,644 control chromosomes in the GnomAD database, including 134,868 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (11295 hom., cov: 17)
  • Exomes 𝑓: 0.52 (123573 hom.)
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.268
• Publications: 26 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 (MetaRNN=0.0011017323).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 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.485T>G	p.Leu162Arg	missense	Exon 3 of 6	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.485T>G	p.Leu162Arg	missense	Exon 3 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000696610.1		n.*390T>G		non_coding_transcript_exon	Exon 4 of 7	ENSP00000512754.1
	HLA-DRB1	ENST00000696611.1		n.408T>G		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.549 AC: 59456 AN: 108304 Hom.: 11275 Cov.: 17

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.563

GnomAD2 exomes AF: 0.656 AC: 142191 AN: 216838 AF XY: 0.655

Gnomad AFR exome AF: 0.719

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.658

GnomAD4 exome AF: 0.516 AC: 574767 AN: 1113244 Hom.: 123573 Cov.: 34 AF XY: 0.524 AC XY: 293028 AN XY: 558954

African (AFR) AF: 0.592 AC: 13293 AN: 22468

American (AMR) AF: 0.581 AC: 23233 AN: 39966

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 14443 AN: 22448

East Asian (EAS) AF: 0.501 AC: 16895 AN: 33752

South Asian (SAS) AF: 0.562 AC: 38049 AN: 67736

European-Finnish (FIN) AF: 0.642 AC: 30386 AN: 47336

Middle Eastern (MID) AF: 0.596 AC: 2689 AN: 4512

European-Non Finnish (NFE) AF: 0.496 AC: 411131 AN: 828290

Other (OTH) AF: 0.527 AC: 24648 AN: 46736

GnomAD4 genome AF: 0.549 AC: 59515 AN: 108400 Hom.: 11295 Cov.: 17 AF XY: 0.543 AC XY: 28257 AN XY: 52028

African (AFR) AF: 0.557 AC: 13806 AN: 24770

American (AMR) AF: 0.536 AC: 5783 AN: 10780

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 1727 AN: 2812

East Asian (EAS) AF: 0.452 AC: 1682 AN: 3720

South Asian (SAS) AF: 0.455 AC: 1421 AN: 3124

European-Finnish (FIN) AF: 0.566 AC: 4122 AN: 7280

Middle Eastern (MID) AF: 0.611 AC: 116 AN: 190

European-Non Finnish (NFE) AF: 0.553 AC: 29594 AN: 53512

Other (OTH) AF: 0.558 AC: 786 AN: 1408

Alfa AF: 0.720 Hom.: 5266

ESP6500AA AF: 0.814 AC: 2455

ESP6500EA AF: 0.822 AC: 4453

ExAC AF: 0.640 AC: 77672

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.029
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	3.5
DANN	Benign	0.17
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.061	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.27
PROVEAN	Benign	4.3	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.056
MPC		1.0
ClinPred		0.000025	T
GERP RS		-0.19
Varity_R		0.12
gMVP		0.32
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs707954; hg19: chr6-32549501; COSMIC: COSV63513549;