Genetic Variant HLA-DRB1:p.Gly164Ser (chr6-32581719-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.490G>A(p.Gly164Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0088 ( 0 hom., cov: 17)

Exomes 𝑓: 0.0018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.55

Publications

8 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=0.008397281).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.490G>A	p.Gly164Ser	missense	Exon 3 of 6	NP_002115.2	P01911

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.490G>A	p.Gly164Ser	missense	Exon 3 of 6	ENSP00000353099.5	P01911
HLA-DRB1	ENST00000963203.1		c.568G>A	p.Gly190Ser	missense	Exon 3 of 6	ENSP00000633262.1
HLA-DRB1	ENST00000859900.1		c.490G>A	p.Gly164Ser	missense	Exon 3 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes

AF:

0.00875

AC:

1022

AN:

116792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.00485

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.00726

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00107

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00410

Gnomad NFE

AF:

0.00748

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00287

AC:

709

AN:

247354

AF XY:

0.00274

show subpopulations

Gnomad AFR exome

AF:

0.00813

Gnomad AMR exome

AF:

0.00552

Gnomad ASJ exome

AF:

0.00241

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00291

Gnomad OTH exome

AF:

0.00634

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00182

AC:

2239

AN:

1228874

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1090

AN XY:

619346

show subpopulations

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

African (AFR)

AF:

0.00339

AC:

AN:

25964

American (AMR)

AF:

0.00279

AC:

117

AN:

41984

Ashkenazi Jewish (ASJ)

AF:

0.00363

AC:

AN:

23408

East Asian (EAS)

AF:

0.00

AC:

AN:

37420

South Asian (SAS)

AF:

0.0000866

AC:

AN:

80852

European-Finnish (FIN)

AF:

0.000350

AC:

AN:

51498

Middle Eastern (MID)

AF:

0.00119

AC:

AN:

5060

European-Non Finnish (NFE)

AF:

0.00193

AC:

1756

AN:

911252

Other (OTH)

AF:

0.00315

AC:

162

AN:

51436

⚠️ 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: 0.251

Heterozygous variant carriers

318

636

953

1271

1589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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: AS_VQSR

AF:

0.00876

AC:

1024

AN:

116886

Hom.:

Cov.:

AF XY:

0.00877

AC XY:

498

AN XY:

56772

show subpopulations

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

African (AFR)

AF:

0.0140

AC:

389

AN:

27698

American (AMR)

AF:

0.0137

AC:

150

AN:

10968

Ashkenazi Jewish (ASJ)

AF:

0.00726

AC:

AN:

2894

East Asian (EAS)

AF:

0.00

AC:

AN:

4260

South Asian (SAS)

AF:

0.00134

AC:

AN:

3740

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

8328

Middle Eastern (MID)

AF:

0.00442

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.00748

AC:

422

AN:

56412

Other (OTH)

AF:

0.0137

AC:

AN:

1536

⚠️ 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: 0.268

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00616

Hom.:

ExAC

AF:

0.0000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.048

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.59

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.0

PhyloP100

1.6

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.17

Sift

Uncertain

0.022

Sift4G

Uncertain

0.035

Polyphen

0.11

Vest4

0.28

MVP

0.29

MPC

1.4

ClinPred

0.081

GERP RS

3.9

Varity_R

0.56

gMVP

0.43

Mutation Taster

=97/3

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