rs142633494
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP3PP5
The NM_001930.4(DHPS):c.1014+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 0 hom. )
Consequence
DHPS
NM_001930.4 splice_donor, intron
NM_001930.4 splice_donor, intron
Scores
2
3
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.34
Genes affected
DHPS (HGNC:2869): (deoxyhypusine synthase) This gene encodes a protein that is required for the formation of hypusine, a unique amino acid formed by the posttranslational modification of only one protein, eukaryotic translation initiation factor 5A. The encoded protein catalyzes the first step in hypusine formation by transferring the butylamine moiety of spermidine to a specific lysine residue of the eukaryotic translation initiation factor 5A precursor, forming an intermediate deoxyhypusine residue. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11261261 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]
PP5
Variant 19-12676016-C-T is Pathogenic according to our data. Variant chr19-12676016-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560196.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=4}. Variant chr19-12676016-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DHPS | NM_001930.4 | c.1014+1G>A | splice_donor_variant, intron_variant | ENST00000210060.12 | NP_001921.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DHPS | ENST00000210060.12 | c.1014+1G>A | splice_donor_variant, intron_variant | 1 | NM_001930.4 | ENSP00000210060.6 | ||||
| ENSG00000285589 | ENST00000648033.1 | n.*559+1G>A | splice_donor_variant, intron_variant | ENSP00000498000.1 |
Frequencies
GnomAD3 genomes 0.000263 AC: 40AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000419 AC: 105AN: 250850Hom.: 0 AF XY: 0.000413 AC XY: 56AN XY: 135588
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GnomAD4 exome AF: 0.000344 AC: 503AN: 1461370Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 254AN XY: 726994
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GnomAD4 genome 0.000263 AC: 40AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurodevelopmental disorder with seizures and speech and walking impairment Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Jan 25, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 23, 2020 | The DHPS c.1014+1G>A variant results in a substitution at the consensus splice acceptor site, which is has been shown to result in removal of coding exons 7 and 8 and a premature termination of the protein (Ganapathi et al. 2019). This variant has been identified in individuals with a phenotype consistent with a neurodevelopmental disorder from two unrelated families (Ganapathi et al. 2019). The highest frequency of this allele in the Genome Aggregation Database is 0.001358 in the Ashkenazi Jewish population (version 2.1.1). Functional studies show that the c.1014+1G>A variant Based on the evidence the c.1014+1G>A variant is classified as likely pathogenic for neurodevelopmental disorder with seizures and speech and walking impairment - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 24, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with seizures and speech and walking impairment (MIM#618480). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. cDNA analysis demonstrates this variant results in exon skipping, however, the protein outcome is uncertain (PMID: 30661771). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (120 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic three times in ClinVar and has been reported as compound heterozygous with p.(Asn173Ser) in three affected individuals from two families (PMID: 30661771). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001930.3:c.518A>G) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 14, 2022 | PS3, PM3, PP1 - |
not provided Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2018 | The c.1014+1G>A variant in the DHPS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 8. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although not identified in the homozygous state, the c.1014+1G>A variant is observed in 13/10,098 (0.13%) alleles from individuals of Ashkenazi Jewish background, and in 118/276,550 total alleles, in large population cohorts (Lek et al., 2016). We interpret c.1014+1G>A as a variant of uncertain significance. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 21, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at