rs142633494

chr19-12676016-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Strong PM2 PP3_Strong PP5

The NM_001930.4(DHPS):c.1014+1G>A variant causes a splice donor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing variant, 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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: {Likely_pathogenic=4, Uncertain_significance=1}. Variant chr19-12676016-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHPS	NM_001930.4	c.1014+1G>A		splice_donor_variant		ENST00000210060.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHPS	ENST00000210060.12	c.1014+1G>A		splice_donor_variant		1	NM_001930.4	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000419 AC: 105 AN: 250850 Hom.: 0 AF XY: 0.000413 AC XY: 56 AN XY: 135588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000344 AC: 503 AN: 1461370 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 254 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.000329

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000539 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with seizures and speech and walking impairment Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 14, 2022	PS3, PM3, PP1 -
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 -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jan 25, 2022	- -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 21, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142633494; hg19: chr19-12786830;