rs200530055

chr17-2036050-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

DPH1
NM_001383.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

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 Uncertain_significance. Variant got 3 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521028.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=1, Pathogenic=1}. 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/exons	MANE	UniProt
DPH1	NM_001383.6 linkuse as main transcript	c.359T>C	p.Leu120Pro	missense_variant	4/13	ENST00000263083.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPH1	ENST00000263083.12 linkuse as main transcript	c.359T>C	p.Leu120Pro	missense_variant	4/13	1	NM_001383.6	P1	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:5

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	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 11, 2022	PS3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	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	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Aug 05, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 30, 2022	- -

PMM2-congenital disorder of glycosylation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 13, 2024

Variant summary: PMM2 c.359T>C (p.Ile120Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.6e-05 in 185580 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (8.6e-05 vs 0.0056), allowing no conclusion about variant significance. c.359T>C has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

DPH1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2023

Published functional studies demonstrate a damaging effect of reduced ADP-ribosylated eEF2 (Urreizti et al., 2020); 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) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2022

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). The heterozygous missense change is ultra rare in healthy individuals:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the DPH1 c.374T>C alteration was observed in 2 among 12,852 total alleles studied (0.02%). In the ExAC database, this alteration was observed in 29 among 119,540 total alleles studied (0.02%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. This variant is reported in the SNPDatabase as rs200530055. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered amino acid is conserved throughout evolution:_x000D_ The p.L125 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico models:_x000D_ The p.L125P alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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;.

MutationTaster

Benign

1.0

D;D

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