14-54941691-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_007086.4(WDHD1):​c.3190-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

WDHD1
NM_007086.4 splice_acceptor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.74
Variant links:
Genes affected
WDHD1 (HGNC:23170): (WD repeat and HMG-box DNA binding protein 1) The protein encoded by this gene contains multiple N-terminal WD40 domains and a C-terminal high mobility group (HMG) box. WD40 domains are found in a variety of eukaryotic proteins and may function as adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly. HMG boxes are found in many eukaryotic proteins involved in chromatin assembly, transcription and replication. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.8088496 fraction of the gene.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WDHD1NM_007086.4 linkc.3190-1G>A splice_acceptor_variant, intron_variant Intron 25 of 25 ENST00000360586.8 NP_009017.1 O75717-1
WDHD1NM_001008396.3 linkc.2821-1G>A splice_acceptor_variant, intron_variant Intron 24 of 24 NP_001008397.1 O75717-2
WDHD1XM_006720012.2 linkc.3184-1G>A splice_acceptor_variant, intron_variant Intron 25 of 25 XP_006720075.1
WDHD1XM_011536373.3 linkc.2101-1G>A splice_acceptor_variant, intron_variant Intron 16 of 16 XP_011534675.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WDHD1ENST00000360586.8 linkc.3190-1G>A splice_acceptor_variant, intron_variant Intron 25 of 25 1 NM_007086.4 ENSP00000353793.3 O75717-1
WDHD1ENST00000420358.2 linkc.2821-1G>A splice_acceptor_variant, intron_variant Intron 24 of 24 5 ENSP00000399349.2 O75717-2
WDHD1ENST00000475379.1 linkn.277-1G>A splice_acceptor_variant, intron_variant Intron 1 of 1 2
WDHD1ENST00000567693.1 linkn.*1640-1G>A splice_acceptor_variant, intron_variant Intron 13 of 13 2 ENSP00000456806.1 H3BSQ1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
33
DANN
Uncertain
0.99
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.83
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.93
Position offset: -2
DS_AL_spliceai
0.99
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.

Other links and lift over

dbSNP: rs1595047164; hg19: chr14-55408409; API