6-32584318-C-T

Variant names:

• chr6-32584318-C-T
• rs17885382
• NM_002124.4:c.161G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002124.4(HLA-DRB1):​c.161G>A​(p.Arg54Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 984,110 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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 0.017 (0 hom., cov: 15)
  • Exomes 𝑓: 0.027 (358 hom.)
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.846
• Publications: 23 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068374574).
• BS2: High Homozygotes in GnomAdExome4 at 358 Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.161G>A	p.Arg54Gln	missense	Exon 2 of 6	NP_002115.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.161G>A	p.Arg54Gln	missense	Exon 2 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000963203.1		c.239G>A	p.Arg80Gln	missense	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.161G>A	p.Arg54Gln	missense	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 1509 AN: 87000 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0584

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.00844

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.00749

Gnomad MID AF: 0.00505

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.000191 AC: 29 AN: 151644 AF XY: 0.000204

Gnomad AFR exome AF: 0.000106

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.000321

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.0271 AC: 24294 AN: 897028 Hom.: 358 Cov.: 23 AF XY: 0.0281 AC XY: 12765 AN XY: 454044

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0170 AC: 438 AN: 25732

American (AMR) AF: 0.0276 AC: 813 AN: 29478

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 528 AN: 16934

East Asian (EAS) AF: 0.00612 AC: 126 AN: 20602

South Asian (SAS) AF: 0.0297 AC: 1855 AN: 62530

European-Finnish (FIN) AF: 0.0118 AC: 439 AN: 37212

Middle Eastern (MID) AF: 0.0615 AC: 270 AN: 4392

European-Non Finnish (NFE) AF: 0.0285 AC: 18891 AN: 662370

Other (OTH) AF: 0.0247 AC: 934 AN: 37778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0173 AC: 1509 AN: 87082 Hom.: 0 Cov.: 15 AF XY: 0.0165 AC XY: 703 AN XY: 42568

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0115 AC: 327 AN: 28414

American (AMR) AF: 0.0153 AC: 118 AN: 7736

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 55 AN: 1832

East Asian (EAS) AF: 0.00850 AC: 21 AN: 2472

South Asian (SAS) AF: 0.0183 AC: 52 AN: 2844

European-Finnish (FIN) AF: 0.00749 AC: 45 AN: 6008

Middle Eastern (MID) AF: 0.00526 AC: 1 AN: 190

European-Non Finnish (NFE) AF: 0.0235 AC: 847 AN: 36008

Other (OTH) AF: 0.0169 AC: 20 AN: 1184

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.120 Hom.: 673

ExAC AF: 0.000355 AC: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.85
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.13
Sift	Uncertain	0.023	D
Sift4G	Benign	0.063	T
Polyphen		0.016	B
Vest4		0.31
MVP		0.17
MPC		0.96
ClinPred		0.026	T
GERP RS		1.7
Varity_R		0.48
gMVP		0.29
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17885382; hg19: chr6-32552095; COSMIC: COSV63513012;