rs757167361

Positions:

• chr17-2030171-T-A
• chr17-2030171-T-C
• chr17-2030171-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001383.6(DPH1):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPH1 NM_001383.6 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.958

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-2030171-T-A is Pathogenic according to our data. Variant chr17-2030171-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218949.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-2030171-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPH1	NM_001383.6	c.2T>A	p.Met1?	start_lost	1/13	ENST00000263083.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPH1	ENST00000263083.12	c.2T>A	p.Met1?	start_lost	1/13	1	NM_001383.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Clinical Genetics Research Group, University of Calgary

-

- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.062
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.63	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.15
Sift	Benign	0.21	T
Sift4G	Benign	0.65	T
Polyphen		0.60	P
Vest4		0.76
MutPred		0.37		Gain of sheet (P = 0.0061);
MVP		0.53
MPC		0.68
ClinPred		0.82	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.44
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs757167361; hg19: chr17-1933465;