Genetic Variant NM_002124.4:c.119C>G (chr6-32584360-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002124.4(HLA-DRB1):c.119C>G(p.Pro40Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.0063 ( 2 hom., cov: 12)

Exomes 𝑓: 0.0095 ( 280 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -14.8

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007349521).

BS2

High Homozygotes in GnomAd4 at 2 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.119C>G	p.Pro40Arg	missense	Exon 2 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.119C>G	p.Pro40Arg	missense	Exon 2 of 6	ENSP00000353099.5
HLA-DRB1	ENST00000696610.1		n.*24C>G		non_coding_transcript_exon	Exon 3 of 7	ENSP00000512754.1
HLA-DRB1	ENST00000696611.1		n.42C>G		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes

AF:

0.00636

AC:

529

AN:

83206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00472

Gnomad AMI

AF:

0.0185

Gnomad AMR

AF:

0.00677

Gnomad ASJ

AF:

0.00624

Gnomad EAS

AF:

0.00253

Gnomad SAS

AF:

0.00523

Gnomad FIN

AF:

0.00308

Gnomad MID

AF:

0.00500

Gnomad NFE

AF:

0.00815

Gnomad OTH

AF:

0.00477

GnomAD2 exomes

AF:

0.000574

AC:

AN:

74940

AF XY:

0.000311

show subpopulations

Gnomad AFR exome

AF:

0.000485

Gnomad AMR exome

AF:

0.000895

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000729

Gnomad NFE exome

AF:

0.000819

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00948

AC:

6498

AN:

685524

Hom.:

280

Cov.:

AF XY:

0.0101

AC XY:

3604

AN XY:

355112

show subpopulations

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

African (AFR)

AF:

0.00748

AC:

148

AN:

19790

American (AMR)

AF:

0.0127

AC:

349

AN:

27588

Ashkenazi Jewish (ASJ)

AF:

0.0131

AC:

210

AN:

16090

East Asian (EAS)

AF:

0.00246

AC:

AN:

25974

South Asian (SAS)

AF:

0.0121

AC:

734

AN:

60444

European-Finnish (FIN)

AF:

0.00781

AC:

277

AN:

35478

Middle Eastern (MID)

AF:

0.0358

AC:

129

AN:

3604

European-Non Finnish (NFE)

AF:

0.00914

AC:

4243

AN:

464176

Other (OTH)

AF:

0.0106

AC:

344

AN:

32380

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.356

Heterozygous variant carriers

322

644

965

1287

1609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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

AF:

0.00633

AC:

527

AN:

83308

Hom.:

Cov.:

AF XY:

0.00567

AC XY:

228

AN XY:

40188

show subpopulations

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

African (AFR)

AF:

0.00471

AC:

117

AN:

24854

American (AMR)

AF:

0.00675

AC:

AN:

7406

Ashkenazi Jewish (ASJ)

AF:

0.00624

AC:

AN:

2082

East Asian (EAS)

AF:

0.00253

AC:

AN:

2762

South Asian (SAS)

AF:

0.00483

AC:

AN:

2484

European-Finnish (FIN)

AF:

0.00308

AC:

AN:

5528

Middle Eastern (MID)

AF:

0.00510

AC:

AN:

196

European-Non Finnish (NFE)

AF:

0.00812

AC:

296

AN:

36442

Other (OTH)

AF:

0.00468

AC:

AN:

1068

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.315

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00208

AC:

172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0010

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.00086

Eigen

Benign

-3.2

Eigen_PC

Benign

-3.3

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.035

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.83

PhyloP100

-15

PROVEAN

Benign

0.080

REVEL

Benign

0.033

Sift

Benign

0.37

Sift4G

Benign

0.37

Polyphen

0.44

Vest4

0.088

MVP

0.085

MPC

0.76

ClinPred

0.013

GERP RS

-7.0

Varity_R

0.13

gMVP

0.41

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over