6-32584354-C-G

Variant summary

Our verdict is Benign. Variant got -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. 12/18 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. R42F) has been classified as Likely benign.

• 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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.125G>C	p.Arg42Thr	missense_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.125G>C	p.Arg42Thr	missense_variant	2/6		NM_002124.4	P1

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

GnomAD3 exomes AF: 0.230 AC: 15271 AN: 66408 Hom.: 6278 AF XY: 0.238 AC XY: 8814 AN XY: 36960

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 SAS exome AF: 0.260

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

Gnomad4 AFR exome AF: 0.507

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.370

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.381

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

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.468

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.420

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.502

ExAC AF: 0.448 AC: 34909

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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: rs1136759; hg19: chr6-32552131; COSMIC: COSV63517285;