Variant 6-32581719-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

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 no assertion criteria provided U:1

Conservation

PhyloP100: 1.55

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008397281).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4 linkuse as main transcript	c.490G>A	p.Gly164Ser	missense_variant	3/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6 linkuse as main transcript	c.490G>A	p.Gly164Ser	missense_variant	3/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

1022

AN:

116792

Hom.:

Cov.:

FAILED QC

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

GnomAD3 exomes

AF:

0.00287

AC:

709

AN:

247354

Hom.:

AF XY:

0.00274

AC XY:

368

AN XY:

134114

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 SAS exome

AF:

0.000262

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

Gnomad4 AFR exome

AF:

0.00339

Gnomad4 AMR exome

AF:

0.00279

Gnomad4 ASJ exome

AF:

0.00363

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000866

Gnomad4 FIN exome

AF:

0.000350

Gnomad4 NFE exome

AF:

0.00193

Gnomad4 OTH exome

AF:

0.00315

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

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.00726

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00134

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00748

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.00616

Hom.:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.32

Cadd

Benign

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over