dbSNP rs201699945: HLA-DRB5:c.764-2A>T (chr6-32518079-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_002125.4(HLA-DRB5):c.764-2A>T 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 1)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB5
NM_002125.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.16

Publications

6 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029962547 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4 link	c.764-2A>T		splice_acceptor_variant, intron_variant	Intron 4 of 5	ENST00000374975.4	NP_002116.2	Q30154A0A2Z4LKS3
HLA-DRB5	XM_011514562.3 link	c.764-2A>T		splice_acceptor_variant, intron_variant	Intron 4 of 5		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4 link	c.764-2A>T		splice_acceptor_variant, intron_variant	Intron 4 of 5	6	NM_002125.4	ENSP00000364114.3		Q30154
HLA-DRB5	ENST00000714490.1 link	c.674-2A>T		splice_acceptor_variant, intron_variant	Intron 4 of 5			ENSP00000519744.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

39548

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

412506

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

209072

African (AFR)

AF:

0.00

AC:

AN:

9702

American (AMR)

AF:

0.00

AC:

AN:

8924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4264

East Asian (EAS)

AF:

0.00

AC:

AN:

12428

South Asian (SAS)

AF:

0.00

AC:

AN:

32188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1366

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

310362

Other (OTH)

AF:

0.00

AC:

AN:

17930

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

39548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

19306

African (AFR)

AF:

0.00

AC:

AN:

10798

American (AMR)

AF:

0.00

AC:

AN:

3012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

538

East Asian (EAS)

AF:

0.00

AC:

AN:

1452

South Asian (SAS)

AF:

0.00

AC:

AN:

1722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

18920

Other (OTH)

AF:

0.00

AC:

AN:

446

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Benign

0.95

Eigen

Uncertain

0.50

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.26

PhyloP100

2.2

GERP RS

4.7

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.76

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over