6-32584354-C-A

Variant names:

• chr6-32584354-C-A
• rs1136759
• NM_002124.4:c.125G>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.125G>T​(p.Arg42Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.15 (2349 hom., cov: 12)
  • Exomes 𝑓: 0.093 (11933 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -11.3
• Publications: 21 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=0.0015797019).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.125G>T	p.Arg42Met	missense_variant	Exon 2 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.125G>T	p.Arg42Met	missense_variant	Exon 2 of 6	6	NM_002124.4	ENSP00000353099.5

Frequencies

GnomAD3 genomes AF: 0.154 AC: 12734 AN: 82950 Hom.: 2349 Cov.: 12

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.0700

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.00891 AC: 592 AN: 66408 AF XY: 0.00828

Gnomad AFR exome AF: 0.00537

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00203

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.00992

Gnomad OTH exome AF: 0.00787

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0933 AC: 67767 AN: 726418 Hom.: 11933 Cov.: 13 AF XY: 0.0922 AC XY: 34728 AN XY: 376754

African (AFR) AF: 0.0529 AC: 1090 AN: 20624

American (AMR) AF: 0.0890 AC: 2699 AN: 30338

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2308 AN: 17612

East Asian (EAS) AF: 0.0496 AC: 1421 AN: 28678

South Asian (SAS) AF: 0.0311 AC: 1976 AN: 63564

European-Finnish (FIN) AF: 0.224 AC: 8462 AN: 37744

Middle Eastern (MID) AF: 0.0425 AC: 163 AN: 3838

European-Non Finnish (NFE) AF: 0.0947 AC: 46324 AN: 489226

Other (OTH) AF: 0.0955 AC: 3324 AN: 34794

GnomAD4 genome AF: 0.153 AC: 12742 AN: 83044 Hom.: 2349 Cov.: 12 AF XY: 0.153 AC XY: 6113 AN XY: 39954

African (AFR) AF: 0.0896 AC: 2244 AN: 25054

American (AMR) AF: 0.157 AC: 1133 AN: 7232

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 442 AN: 2110

East Asian (EAS) AF: 0.0268 AC: 72 AN: 2688

South Asian (SAS) AF: 0.0543 AC: 131 AN: 2412

European-Finnish (FIN) AF: 0.300 AC: 1609 AN: 5360

Middle Eastern (MID) AF: 0.0765 AC: 15 AN: 196

European-Non Finnish (NFE) AF: 0.185 AC: 6759 AN: 36454

Other (OTH) AF: 0.152 AC: 160 AN: 1054

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0250 AC: 1950

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0020
DANN	Benign	0.40
DEOGEN2	Benign	0.00064	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.031	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.62	T
PhyloP100		-11
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.75	P
Vest4		0.17
MPC		1.2
ClinPred		0.075	T
GERP RS		-7.0
Varity_R		0.13
gMVP		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs1136759; hg19: chr6-32552131;