Variant 6-32518079-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PVS1_ModerateBP6_Moderate

The NM_002125.4(HLA-DRB5):c.764-2A>G variant causes a splice acceptor, intron 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 Benign (★).

Frequency

Genomes: 𝑓 0.00025 ( 1 hom., cov: 1)

Exomes 𝑓: 0.000036 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB5
NM_002125.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.16

Variant links:

Genes affected

HLA-DRB5 (HGNC:4953): (major histocompatibility complex, class II, DR beta 5) HLA-DRB5 belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DRA) and a beta (DRB) chain, 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 and its gene contains 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. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. There are multiple pseudogenes of this gene. [provided by RefSeq, Feb 2020]

HLA-DRB5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.028714107 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.1, offset of 24, new splice context is: ctctggacttcacccaacAGgta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 6-32518079-T-C is Benign according to our data. Variant chr6-32518079-T-C is described in ClinVar as [Benign]. Clinvar id is 252598.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4 link	c.764-2A>G		splice_acceptor_variant, intron_variant		ENST00000374975.4	NP_002116.2	Q30154A0A2Z4LKS3
HLA-DRB5	XM_011514562.3 link	c.764-2A>G		splice_acceptor_variant, intron_variant			XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4 link	c.764-2A>G		splice_acceptor_variant, intron_variant		6	NM_002125.4	ENSP00000364114.3		Q30154

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

39418

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000333

Gnomad ASJ

AF:

0.00187

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000410

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000212

Gnomad OTH

AF:

0.00227

GnomAD3 exomes

AF:

0.000950

AC:

AN:

71566

Hom.:

AF XY:

0.00119

AC XY:

AN XY:

39460

show subpopulations

Gnomad AFR exome

AF:

0.000222

Gnomad AMR exome

AF:

0.000288

Gnomad ASJ exome

AF:

0.00117

Gnomad EAS exome

AF:

0.000191

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00100

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000364

AC:

AN:

412464

Hom.:

Cov.:

AF XY:

0.0000478

AC XY:

AN XY:

209056

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000457

Gnomad4 NFE exome

AF:

0.0000258

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000254

AC:

AN:

39438

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

AN XY:

19264

show subpopulations

Gnomad4 AFR

AF:

0.000185

Gnomad4 AMR

AF:

0.000332

Gnomad4 ASJ

AF:

0.00187

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000410

Gnomad4 NFE

AF:

0.000212

Gnomad4 OTH

AF:

0.00219

Alfa

AF:

0.0388

Hom.:

ExAC

AF:

0.00472

AC:

342

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 13, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

DANN

Benign

0.95

Eigen

Uncertain

0.50

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.24

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.98

Position offset: -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