rs200530055

Variant names:

Variant summary

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

The NM_001383.6(DPH1):c.359T>C(p.Leu120Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000496 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

DPH1
NM_001383.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.00

Variant links:

Genes affected

DPH1 (HGNC:3003): (diphthamide biosynthesis 1) The protein encoded by this gene is an enzyme involved in the biosynthesis of diphthamide, a modified histidine found only in elongation factor-2 (EEF2). Diphthamide residues in EEF2 are targeted for ADP-ribosylation by diphtheria toxin and Pseudomonas exotoxin A. Defects in this gene have been associated with both ovarian cancer and autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. [provided by RefSeq, Oct 2016]

DPH1 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 17-2036050-T-C is Pathogenic according to our data. Variant chr17-2036050-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2036050-T-C is described in Lovd as [Pathogenic]. Variant chr17-2036050-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPH1	NM_001383.6 link	c.359T>C	p.Leu120Pro	missense_variant	Exon 4 of 13	ENST00000263083.12	NP_001374.4	Q9BZG8-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPH1	ENST00000263083.12 link	c.359T>C	p.Leu120Pro	missense_variant	Exon 4 of 13	1	NM_001383.6	ENSP00000263083.7		Q9BZG8-4

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000289

AC:

AN:

248874

Hom.:

AF XY:

0.000333

AC XY:

AN XY:

135294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000426

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000517

AC:

756

AN:

1461728

Hom.:

Cov.:

AF XY:

0.000495

AC XY:

360

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000761

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000614

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000289

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000385

Hom.:

Bravo

AF:

0.000382

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000948

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental delay with short stature, dysmorphic facial features, and sparse hair

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Aug 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.029%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 30877278). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 3CNET). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521028). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 30877278). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 11, 2022	PS3, PM3 -

Developmental delay with short stature, dysmorphic facial features, and sparse hair 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 30, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2024	Variant summary: DPH1 c.359T>C (p.Leu120Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 248874 control chromosomes. This frequency does not allow conclusion about variant significance. c.359T>C has been reported in the literature in 2 homozygous siblings affected with Developmental Delay With Short Stature, Dysmorphic Facial Features, And Sparse Hair 1 (Lefebvre_2021, Urreizti_2020) . These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating reduced amounts of ADP-ribosylated eEF2 (Urreizti_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32732226, 30877278). ClinVar contains an entry for this variant (Variation ID: 521028). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.374T>C (p.L125P) alteration is located in coding exon 4 of the DPH1 gene. This alteration results from a T to C substitution at nucleotide position 374, causing the leucine (L) at amino acid position 125 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.029% (80/280222) total alleles studied. The highest observed frequency was 0.059% (21/35334) of Latino alleles. This variant has been identified in the homozygous state and/or in conjunction with other DPH1 variant(s) in individual(s) with features consistent with DPH1-related neurodevelopmental disorder (Ambry internal data; Urreizti, 2020; Lefebvre, 2021; Faas, 2023; Drexler, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

DPH1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The DPH1 c.374T>C variant is predicted to result in the amino acid substitution p.Leu125Pro. This variant in the homozygous state has been reported in a neonatal patient who was diagnosed with structural anomalies such as birth defects, dysmorphic features, cardiac, craniofacial, and skeletal defects (Powis et al. 2018. PubMed ID: 29565416, Supplementary Table 1). This variant was also reported in the homozygous state in two siblings presenting with a variety of features including developmental delay, central nervous system malformations, short stature, unusual skull shape, and genital anomalies (Urreizti et al. 2020. PubMed ID: 30877278), and a fetus with multiple congenital abnormalities (Lefebvre et al. 2021. PubMed ID: 32732226). Functional studies of DPH1 p.Leu125Pro showed reduced enzyme activity (Urreizti et al. 2020. PubMed ID: 30877278). This variant is reported in 0.059% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 22, 2024

Published functional studies demonstrate a damaging effect of reduced ADP-ribosylated eEF2 (PMID: 30877278); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26220823, 25558065, 29565416, 24895408, 14744934, 30877278, 32732226, 34297361, 27460824, 26415585, 33704902, 37675463, 36647814, 37326029) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.5

H;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.8

D;.

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.97

MVP

0.82

MPC

0.75

ClinPred

0.48

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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