6-32584354-C-G

Variant names:

• chr6-32584354-C-G
• rs1136759
• NM_002124.4:c.125G>C

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>C​(p.Arg42Thr) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R42S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.46 (10612 hom., cov: 12)
  • Exomes 𝑓: 0.35 (75170 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=6.367564E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.125G>C	p.Arg42Thr	missense	Exon 2 of 6	NP_002115.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.125G>C	p.Arg42Thr	missense	Exon 2 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000963203.1		c.203G>C	p.Arg68Thr	missense	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.125G>C	p.Arg42Thr	missense	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 36008 AN: 78704 Hom.: 10600 Cov.: 12

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.230 AC: 15271 AN: 66408 AF XY: 0.238

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.0956

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.289

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.347 AC: 241747 AN: 696876 Hom.: 75170 Cov.: 13 AF XY: 0.362 AC XY: 130722 AN XY: 361340

African (AFR) AF: 0.507 AC: 9829 AN: 19400

American (AMR) AF: 0.432 AC: 12433 AN: 28750

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 9445 AN: 17174

East Asian (EAS) AF: 0.370 AC: 9963 AN: 26962

South Asian (SAS) AF: 0.473 AC: 27697 AN: 58526

European-Finnish (FIN) AF: 0.311 AC: 11470 AN: 36922

Middle Eastern (MID) AF: 0.584 AC: 2128 AN: 3646

European-Non Finnish (NFE) AF: 0.309 AC: 146138 AN: 472276

Other (OTH) AF: 0.381 AC: 12644 AN: 33220

GnomAD4 genome AF: 0.458 AC: 36048 AN: 78790 Hom.: 10612 Cov.: 12 AF XY: 0.452 AC XY: 17115 AN XY: 37878

African (AFR) AF: 0.542 AC: 12943 AN: 23878

American (AMR) AF: 0.468 AC: 3214 AN: 6866

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1092 AN: 2048

East Asian (EAS) AF: 0.454 AC: 1160 AN: 2556

South Asian (SAS) AF: 0.420 AC: 933 AN: 2220

European-Finnish (FIN) AF: 0.264 AC: 1343 AN: 5086

Middle Eastern (MID) AF: 0.663 AC: 122 AN: 184

European-Non Finnish (NFE) AF: 0.423 AC: 14590 AN: 34498

Other (OTH) AF: 0.502 AC: 502 AN: 1000

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.448 AC: 34909

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0010
DANN	Benign	0.18
DEOGEN2	Benign	0.00058	T
Eigen	Benign	-2.9
Eigen_PC	Benign	-3.1
FATHMM_MKL	Benign	0.00077	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.00064	T
MetaSVM	Benign	-0.74	T
PhyloP100		-11
PROVEAN	Benign	0.57	N
REVEL	Benign	0.067
Sift	Benign	0.34	T
Sift4G	Benign	0.37	T
Polyphen		0.083	B
Vest4		0.15
MPC		1.2
ClinPred		0.028	T
GERP RS		-7.0
Varity_R		0.18
gMVP		0.25
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; COSMIC: COSV63517285;