rs758100382

Positions:

chr19-12679696-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001930.4(DHPS):c.518A>G(p.Asn173Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

DHPS
NM_001930.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.88

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-12679696-T-C is Pathogenic according to our data. Variant chr19-12679696-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12679696-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHPS	NM_001930.4 linkuse as main transcript	c.518A>G	p.Asn173Ser	missense_variant	4/9	ENST00000210060.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHPS	ENST00000210060.12 linkuse as main transcript	c.518A>G	p.Asn173Ser	missense_variant	4/9	1	NM_001930.4	P1	P49366-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251482

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000992

AC:

145

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with seizures and speech and walking impairment

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 22, 2020	The DHPS c.518A>G (p.Asn173Ser) variant is a missense variant, which has been identified in a compound heterozygous state in at least five individuals with neurodevelopmental disorder from four unrelated families (Ganapathi et al. 2019). The p.Asn173Ser variant is reported at a frequency of 0.000116 in the European (non-Finnish) population in the Genome Aggregation Database (version 2.1.1). Functional studies demonstrate that the p.(Asn173Ser) variant exhibited partial enzymatic activity, ranging from 18% to 25% of that of wild-type DHPS resulting in impaired biosynthesis of deoxyhypusine (Ganapathi et al. 2019). Based on the collective evidence the c.518A>G (p.Asn173Ser) variant is classified as pathogenic for neurodevelopmental disorder with seizures and speech and walking impairment. -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 22, 2019	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, PP3, PP1, PM3, PS3-Moderate. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2019	- -

DHPS-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2023

The DHPS c.518A>G variant is predicted to result in the amino acid substitution p.Asn173Ser. This variant was reported in the compound heterozygous state, in trans with a predicted loss-of-function variant, in all five affected individuals described in the DHPS index study (Ganapathi et al 2019. PubMed ID: 30661771). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-12790510-T-C). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2022

In vitro assays demonstrate N173S loss of function (Ganapathi M, 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30661771, 34273022) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.;.;.;T;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.68

D;D;D;D;D;D

MetaSVM

Benign

-0.31

MutationAssessor

Pathogenic

3.3

M;M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.8

D;D;.;.;.;.

REVEL

Uncertain

0.35

Sift

Benign

0.034

D;D;.;.;.;.

Sift4G

Benign

0.13

T;T;T;T;.;D

Polyphen

0.95

P;P;.;.;.;.

Vest4

0.28

MVP

0.47

MPC

0.52

ClinPred

0.86

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over