rs707954

Positions:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011017323).
• BP6: Variant 6-32581724-A-C is Benign according to our data. Variant chr6-32581724-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.485T>G	p.Leu162Arg	missense_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.485T>G	p.Leu162Arg	missense_variant	3/6		NM_002124.4	ENSP00000353099	P1

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

GnomAD3 exomes AF: 0.656 AC: 142191 AN: 216838 Hom.: 39557 AF XY: 0.655 AC XY: 77406 AN XY: 118260

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 SAS exome AF: 0.640

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

Gnomad4 AFR exome AF: 0.592

Gnomad4 AMR exome AF: 0.581

Gnomad4 ASJ exome AF: 0.643

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.562

Gnomad4 FIN exome AF: 0.642

Gnomad4 NFE exome AF: 0.496

Gnomad4 OTH exome AF: 0.527

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

Gnomad4 AFR AF: 0.557

Gnomad4 AMR AF: 0.536

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.566

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.558

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 v4.3

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
MutationTaster	Benign	1.0	P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs707954; hg19: chr6-32549501; COSMIC: COSV63513549;