Genetic Variant DPH1:p.Gln12* (chr17-2030203-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_001383.6(DPH1):c.34C>T(p.Gln12*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

DPH1
NM_001383.6 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.296

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

developmental delay with short stature, dysmorphic facial features, and sparse hair
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental delay with short stature, dysmorphic facial features, and sparse hair 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome
Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

DPH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001383.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPH1	NM_001383.6	MANE Select	c.34C>T	p.Gln12*	stop_gained	Exon 1 of 13	NP_001374.4	Q9BZG8-4
DPH1	NM_001346574.1		c.49C>T	p.Gln17*	stop_gained	Exon 1 of 13	NP_001333503.1
DPH1	NM_001346575.1		c.49C>T	p.Gln17*	stop_gained	Exon 1 of 13	NP_001333504.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPH1	ENST00000263083.12	TSL:1 MANE Select	c.34C>T	p.Gln12*	stop_gained	Exon 1 of 13	ENSP00000263083.7	Q9BZG8-4
DPH1	ENST00000575667.6	TSL:1	n.43C>T		non_coding_transcript_exon	Exon 1 of 12	ENSP00000460431.2	A0A0A0MTR4
DPH1	ENST00000674200.2		c.49C>T	p.Gln17*	stop_gained	Exon 1 of 13	ENSP00000501368.1	Q9BZG8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

220228

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.21

Eigen_PC

Benign

-0.077

FATHMM_MKL

Benign

0.00040

PhyloP100

-0.30

Vest4

0.64

GERP RS

2.7

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=33/167

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over