rs541400419

Variant names:

• chr19-12679833-CCT-C
• rs541400419
• NM_001930.4:c.460_461delAG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001930.4(DHPS):​c.460_461delAG​(p.Arg154GlyfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: DHPS NM_001930.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.212

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-12679833-CCT-C is Pathogenic according to our data. Variant chr19-12679833-CCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1702982.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHPS	NM_001930.4	c.460_461delAG	p.Arg154GlyfsTer11	frameshift_variant	Exon 3 of 9	ENST00000210060.12	NP_001921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHPS	ENST00000210060.12	c.460_461delAG	p.Arg154GlyfsTer11	frameshift_variant	Exon 3 of 9	1	NM_001930.4	ENSP00000210060.6
ENSG00000285589	ENST00000648033.1	n.*5_*6delAG		non_coding_transcript_exon_variant	Exon 3 of 14			ENSP00000498000.1
ENSG00000285589	ENST00000648033.1	n.*5_*6delAG		3_prime_UTR_variant	Exon 3 of 14			ENSP00000498000.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250552 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135444

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000828 AC: 121 AN: 1461864 Hom.: 0 AF XY: 0.0000976 AC XY: 71 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000845

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74366

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with seizures and speech and walking impairment Pathogenic:1

Aug 10, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.460_461delp.(Arg154Glyfs*11) is a null frameshift variant (NMD) in the DHPS gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. The variant is present at low allele frequencies population databases (rs541400419 – gnomAD 0.0007884%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

not provided Uncertain:1

Sep 10, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs541400419; hg19: chr19-12790647;