1-43970708-G-T

Position:

• chr1-43970708-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001319167.2(DPH2):​c.-429G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DPH2 NM_001319167.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.10

Genes affected

DPH2 (HGNC:3004): (diphthamide biosynthesis 2) This gene is one of two human genes similar to the yeast gene dph2. The yeast gene was identified by its ability to complement a diphthamide mutant strain, and thus probably functions in diphthamide biosynthesis. Diphthamide is a post-translationally modified histidine residue present in elongation factor 2 (EF2) that is the target of diphtheria toxin ADP-ribosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

DPH2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPH2	NM_001384.5	c.260G>T	p.Ser87Ile	missense_variant, splice_region_variant	2/6	ENST00000255108.8	NP_001375.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPH2	ENST00000255108.8	c.260G>T	p.Ser87Ile	missense_variant, splice_region_variant	2/6	1	NM_001384.5	ENSP00000255108.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Global developmental delay;C2243051:Macrocephaly;C3714756:Intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Oct 16, 2019

DPH2 encodes for Diphthamide Biosynthesis Protein 2, one of several enzymes involved in synthesis of diphthamide in translation elongation factor-2 (EEF2). Diphthamide is a unique posttranslationally modified histidine found only in EEF2. This modification is conserved from archaebacteria to humans and serves as the target for ADP-ribosylation and inactivation of EEF2 by diphtheria toxin and Pseudomonas exotoxin A. DPH2 interacts with it's paralog protein DPH1 and previous studies suggested that these enzymes may function in diphthamide biosynthesis as a dimer or multimer (Liu et al. Molec Cell Biol 2004). Recently autosomal recessive variants in DPH1 gene have been associated with a rare neurodevelopmental disorder, known as Developmental delay with short stature, dysmorphic features, and sparse hair (MIM #616901), with clinical features, including intellectual disability, short stature, and craniofacial and ectodermal anomalies (Urreizti et al. Eur J Hum Genet 2019). The c.260G>T variant is not present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP. The variant is also not present in our in-house exome database. The variant was also not reported to OMIM, ClinVar and Human Genome Mutation Database (HGMD) in any other affected individuals. In-silico splice-site aberration prediction program Human Splice Finder version 3.1 (HSF3.1) predicted possible effect of splicing due to alteration of the wild type donor site and creation of an exonic ESS (Exonic Splicing Silencer) region by this variant. In-silico pathogenicity prediction programs like Mutation Taster2, CADD etc. predicted this variant as likely disease causing. Since the variant has not been associated with any disorder till date and because it is a missense variant with no experimentally proven functional effect, the variant has been classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.83		Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);
MVP		0.81
MPC		0.95
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 18
DS_DL_spliceai		0.95		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1571781453; hg19: chr1-44436380;