19-12679696-TT-GA

Variant names:

• chr19-12679696-TT-GA
• NM_001930.4:c.517_518delAAinsTC
• DHPS p.Asn173Ser

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1_Very_Strong

The NM_001930.4(DHPS):​c.517_518delAAinsTC​(p.Asn173Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHPS NM_001930.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.95
• Publications: 0 publications found

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]

DHPS Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with seizures and speech and walking impairment

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P

ENSG00000285589 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_001930.4 (DHPS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001930.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHPS	NM_001930.4	MANE Select	c.517_518delAAinsTC	p.Asn173Ser	missense	N/A	NP_001921.1	P49366-1
	DHPS	NM_001369691.1		c.517_518delAAinsTC	p.Asn173Ser	missense	N/A	NP_001356620.1
	DHPS	NM_001206974.2		c.391_392delAAinsTC	p.Asn131Ser	missense	N/A	NP_001193903.1	P49366-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHPS	ENST00000210060.12	TSL:1 MANE Select	c.517_518delAAinsTC	p.Asn173Ser	missense	N/A	ENSP00000210060.6	P49366-1
	DHPS	ENST00000351660.9	TSL:1	c.517_518delAAinsTC	p.Asn173Ser	missense	N/A	ENSP00000221303.5	P49366-2
	DHPS	ENST00000601537.5	TSL:1	n.517_518delAAinsTC		non_coding_transcript_exon	Exon 4 of 8	ENSP00000472122.1	Q5J8M5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-12790510;