Genetic Variant HLA-DRB1:p.Arg42Lys (chr6-32584354-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002124.4(HLA-DRB1):c.125G>A(p.Arg42Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 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: 12)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -11.3

Publications

21 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016403288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4 link	c.125G>A	p.Arg42Lys	missense_variant	Exon 2 of 6	ENST00000360004.6	NP_002115.2	P01911D7RIH8A0A224MM52X5DNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6 link	c.125G>A	p.Arg42Lys	missense_variant	Exon 2 of 6	6	NM_002124.4	ENSP00000353099.5		P01911

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

83212

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

GnomAD2 exomes

AF:

0.000120

AC:

AN:

66408

AF XY:

0.000108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000735

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000711

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000938

AC:

AN:

746492

Hom.:

Cov.:

AF XY:

0.00000517

AC XY:

AN XY:

386690

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20990

American (AMR)

AF:

0.000195

AC:

AN:

30768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17994

East Asian (EAS)

AF:

0.00

AC:

AN:

28790

South Asian (SAS)

AF:

0.00

AC:

AN:

64014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3880

European-Non Finnish (NFE)

AF:

0.00000198

AC:

AN:

505768

Other (OTH)

AF:

0.00

AC:

AN:

35536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.782

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

83212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

40004

African (AFR)

AF:

0.00

AC:

AN:

25056

American (AMR)

AF:

0.00

AC:

AN:

7246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2120

East Asian (EAS)

AF:

0.00

AC:

AN:

2696

South Asian (SAS)

AF:

0.00

AC:

AN:

2414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

200

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

36562

Other (OTH)

AF:

0.00

AC:

AN:

1036

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000257

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0010

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.00067

Eigen

Benign

-2.9

Eigen_PC

Benign

-3.1

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.0071

M_CAP

Benign

0.0018

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.71

PhyloP100

-11

PROVEAN

Benign

0.24

REVEL

Benign

0.043

Sift

Benign

0.29

Sift4G

Benign

0.29

Polyphen

0.030

Vest4

0.099

MVP

0.15

MPC

0.79

ClinPred

0.095

GERP RS

-7.0

Varity_R

0.25

gMVP

0.34

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over