chr6-32584354-C-A

Position:

• chr6-32584354-C-A

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>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. 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 0.15 (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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.125G>T	p.Arg42Met	missense_variant	2/6	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.125G>T	p.Arg42Met	missense_variant	2/6	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

GnomAD3 exomes AF: 0.00891 AC: 592 AN: 66408 Hom.: 56 AF XY: 0.00828 AC XY: 306 AN XY: 36960

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 SAS exome AF: 0.00459

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

Gnomad4 AFR exome AF: 0.0529

Gnomad4 AMR exome AF: 0.0890

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.0496

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.0947

Gnomad4 OTH exome AF: 0.0955

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

Gnomad4 AFR AF: 0.0896

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.0268

Gnomad4 SAS AF: 0.0543

Gnomad4 FIN AF: 0.300

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.152

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
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

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;