Variant chr6-32580745-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PVS1_StrongPP3BP6_Moderate

The NM_002124.4(HLA-DRB1):c.763+1G>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.31

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 Uncertain_significance. Variant got 3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13732834 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP3

Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP6

Variant 6-32580745-C-G is Benign according to our data. Variant chr6-32580745-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3024757.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4 linkuse as main transcript	c.763+1G>C		splice_donor_variant		ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6 linkuse as main transcript	c.763+1G>C		splice_donor_variant			NM_002124.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

322

AN:

140036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000921

Gnomad AMI

AF:

0.00495

Gnomad AMR

AF:

0.00342

Gnomad ASJ

AF:

0.00504

Gnomad EAS

AF:

0.00412

Gnomad SAS

AF:

0.00113

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00350

Gnomad NFE

AF:

0.00292

Gnomad OTH

AF:

0.00107

GnomAD3 exomes

AF:

0.0186

AC:

3671

AN:

197302

Hom.:

AF XY:

0.0184

AC XY:

1959

AN XY:

106472

show subpopulations

Gnomad AFR exome

AF:

0.00711

Gnomad AMR exome

AF:

0.0227

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.0169

Gnomad SAS exome

AF:

0.00969

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00343

AC:

4444

AN:

1294940

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

2059

AN XY:

647198

show subpopulations

Gnomad4 AFR exome

AF:

0.00104

Gnomad4 AMR exome

AF:

0.00253

Gnomad4 ASJ exome

AF:

0.00143

Gnomad4 EAS exome

AF:

0.000455

Gnomad4 SAS exome

AF:

0.000431

Gnomad4 FIN exome

AF:

0.000292

Gnomad4 NFE exome

AF:

0.00417

Gnomad4 OTH exome

AF:

0.00291

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00230

AC:

322

AN:

140148

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

150

AN XY:

68176

show subpopulations

Gnomad4 AFR

AF:

0.000918

Gnomad4 AMR

AF:

0.00341

Gnomad4 ASJ

AF:

0.00504

Gnomad4 EAS

AF:

0.00413

Gnomad4 SAS

AF:

0.00113

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00292

Gnomad4 OTH

AF:

0.00106

Alfa

AF:

0.0277

Hom.:

ExAC

AF:

0.101

AC:

12269

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

HLA-DRB1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

GERP RS

4.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: 1

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