19-12676113-GATGTAA-G

Variant names:

• chr19-12676113-GATGTAA-G
• rs1568317152
• NM_001930.4:c.912_917delTTACAT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_Very_Strong

The NM_001930.4(DHPS):​c.912_917delTTACAT​(p.Tyr305_Ile306del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,226 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DHPS NM_001930.4 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 8.68

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]

ENSG00000285589 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001930.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-12676113-GATGTAA-G is Pathogenic according to our data. Variant chr19-12676113-GATGTAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12676113-GATGTAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHPS	NM_001930.4	c.912_917delTTACAT	p.Tyr305_Ile306del	disruptive_inframe_deletion	Exon 8 of 9	ENST00000210060.12	NP_001921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHPS	ENST00000210060.12	c.912_917delTTACAT	p.Tyr305_Ile306del	disruptive_inframe_deletion	Exon 8 of 9	1	NM_001930.4	ENSP00000210060.6
ENSG00000285589	ENST00000648033.1	n.*457_*462delTTACAT		non_coding_transcript_exon_variant	Exon 8 of 14			ENSP00000498000.1
ENSG00000285589	ENST00000648033.1	n.*457_*462delTTACAT		3_prime_UTR_variant	Exon 8 of 14			ENSP00000498000.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461226 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726900

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with seizures and speech and walking impairment Pathogenic:2

Jun 24, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 22, 2019

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely pathogenic for Neurodevelopmental disorder with seizures and speech and walking impairment, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PM3, PS3-Moderate. -

DHPS-related disorder Pathogenic:1

Sep 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DHPS c.912_917del6 variant is predicted to result in an in-frame deletion (p.Tyr305_Ile306del). This variant has been reported in the compound heterozygous state with a second putative disease-allele in an individual with neurodevelopmental delay and seizures (Ganapathi et al. 2019. PubMed ID: 30661771). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare in the general population. Functional analysis indicated that this variant strongly reduces DHPS enzyme activity (Ganapathi et al. 2019. PubMed ID: 30661771; Padgett et al. 2023. PubMed ID: 37333770). Taken together, this variant is classified as likely pathogenic. -

not provided Uncertain:1

Aug 01, 2018

GeneDx

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The c.912_917delTTACAT variant in the DHPS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.912_917delTTACAT variant causes an in-frame deletion of two amino acids, Tyrosine 305 and Isoleucine 306, denoted p.Tyr305_Ile306del. The Y305 residue is not conserved, and for the I306 residue, amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The c.912_917delTTACAT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.912_917delTTACAT as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1568317152; hg19: chr19-12786927;