Genetic Variant HLA-DRB1:p.Leu162Pro (chr6-32581724-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002124.4(HLA-DRB1):c.485T>C(p.Leu162Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0 ( 0 hom., cov: 17)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.268

Publications

26 publications found

Variant links:

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

HLA-DRB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14372826).

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.485T>C	p.Leu162Pro	missense	Exon 3 of 6	NP_002115.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.485T>C	p.Leu162Pro	missense	Exon 3 of 6	ENSP00000353099.5
HLA-DRB1	ENST00000696610.1		n.*390T>C		non_coding_transcript_exon	Exon 4 of 7	ENSP00000512754.1
HLA-DRB1	ENST00000696611.1		n.408T>C		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

114542

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1231676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

620716

African (AFR)

AF:

0.00

AC:

AN:

25984

American (AMR)

AF:

0.00

AC:

AN:

42652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24192

East Asian (EAS)

AF:

0.00

AC:

AN:

36944

South Asian (SAS)

AF:

0.00

AC:

AN:

79344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4978

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

914326

Other (OTH)

AF:

0.00

AC:

AN:

51940

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

114542

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

54914

African (AFR)

AF:

0.00

AC:

AN:

26686

American (AMR)

AF:

0.00

AC:

AN:

11194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2898

East Asian (EAS)

AF:

0.00

AC:

AN:

3928

South Asian (SAS)

AF:

0.00

AC:

AN:

3356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56366

Other (OTH)

AF:

0.00

AC:

AN:

1470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.019

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.045

M_CAP

Benign

0.0097

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.2

PhyloP100

-0.27

PROVEAN

Benign

-0.50

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

0.0040

Vest4

0.15

MutPred

0.53

Gain of disorder (P = 0.023)

MVP

0.37

MPC

1.1

ClinPred

0.78

GERP RS

-0.19

Varity_R

0.76

gMVP

0.77

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over