6-32584318-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_002124.4(HLA-DRB1):​c.161G>T​(p.Arg54Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.744

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>T	p.Arg54Leu	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>T	p.Arg54Leu	missense	Exon 2 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000963203.1		c.239G>T	p.Arg80Leu	missense	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.161G>T	p.Arg54Leu	missense	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 934632 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 473576

African (AFR) AF: 0.00 AC: 0 AN: 26676

American (AMR) AF: 0.00 AC: 0 AN: 30800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17968

East Asian (EAS) AF: 0.00 AC: 0 AN: 20804

South Asian (SAS) AF: 0.00 AC: 0 AN: 65724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 690986

Other (OTH) AF: 0.00 AC: 0 AN: 39184

GnomAD4 genome Cov.: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0021	T
MetaRNN	Pathogenic	0.74	D
MetaSVM	Benign	-0.97	T
PhyloP100		0.85
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.13
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.56	P
Vest4		0.58
MutPred		0.67		Loss of sheet (P = 0.0817)
MVP		0.51
MPC		1.1
ClinPred		0.69	D
GERP RS		1.7
Varity_R		0.61
gMVP		0.54
Mutation Taster		=98/2	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;