Genetic Variant HLA-DRB1:p.Pro40Ala (chr6-32584361-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002124.4(HLA-DRB1):c.118C>G(p.Pro40Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.033 ( 119 hom., cov: 11)

Exomes 𝑓: 0.031 ( 4199 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -10.4

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.

BS2

High Homozygotes in GnomAd4 at 119 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4 link	c.118C>G	p.Pro40Ala	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.118C>G	p.Pro40Ala	missense_variant	Exon 2 of 6	6	NM_002124.4	ENSP00000353099.5		P01911

Frequencies

GnomAD3 genomes

AF:

0.0330

AC:

2490

AN:

75346

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.0764

Gnomad AMR

AF:

0.0411

Gnomad ASJ

AF:

0.0517

Gnomad EAS

AF:

0.0322

Gnomad SAS

AF:

0.0233

Gnomad FIN

AF:

0.0266

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.0412

Gnomad OTH

AF:

0.0243

GnomAD2 exomes

AF:

0.00590

AC:

380

AN:

64458

AF XY:

0.00593

show subpopulations

Gnomad AFR exome

AF:

0.00194

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.00844

Gnomad EAS exome

AF:

0.00455

Gnomad FIN exome

AF:

0.00427

Gnomad NFE exome

AF:

0.00540

Gnomad OTH exome

AF:

0.00513

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0314

AC:

21521

AN:

685612

Hom.:

4199

Cov.:

AF XY:

0.0323

AC XY:

11452

AN XY:

354962

show subpopulations

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

African (AFR)

AF:

0.0150

AC:

286

AN:

19020

American (AMR)

AF:

0.0533

AC:

1471

AN:

27588

Ashkenazi Jewish (ASJ)

AF:

0.0417

AC:

669

AN:

16060

East Asian (EAS)

AF:

0.0377

AC:

980

AN:

25978

South Asian (SAS)

AF:

0.0495

AC:

2926

AN:

59054

European-Finnish (FIN)

AF:

0.0249

AC:

890

AN:

35746

Middle Eastern (MID)

AF:

0.0468

AC:

171

AN:

3650

European-Non Finnish (NFE)

AF:

0.0278

AC:

12953

AN:

465796

Other (OTH)

AF:

0.0359

AC:

1175

AN:

32720

⚠️ 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: 0.384

Heterozygous variant carriers

701

1402

2104

2805

3506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0330

AC:

2489

AN:

75434

Hom.:

119

Cov.:

AF XY:

0.0302

AC XY:

1098

AN XY:

36390

show subpopulations

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

African (AFR)

AF:

0.0194

AC:

446

AN:

23020

American (AMR)

AF:

0.0409

AC:

273

AN:

6668

Ashkenazi Jewish (ASJ)

AF:

0.0517

AC:

101

AN:

1952

East Asian (EAS)

AF:

0.0331

AC:

AN:

2384

South Asian (SAS)

AF:

0.0224

AC:

AN:

2144

European-Finnish (FIN)

AF:

0.0266

AC:

129

AN:

4852

Middle Eastern (MID)

AF:

0.0291

AC:

AN:

172

European-Non Finnish (NFE)

AF:

0.0412

AC:

1354

AN:

32872

Other (OTH)

AF:

0.0239

AC:

AN:

964

⚠️ 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: 0.371

Heterozygous variant carriers

123

245

368

490

613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.103

Hom.:

ExAC

AF:

0.114

AC:

8811

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.0010

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.00065

Eigen

Benign

-3.1

Eigen_PC

Benign

-3.2

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.040

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.95

PhyloP100

-10

PROVEAN

Benign

1.8

REVEL

Benign

0.028

Sift

Benign

0.65

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.057

MPC

0.69

ClinPred

0.0054

GERP RS

-7.0

Varity_R

0.10

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over