dbSNP rs116911386: DPH1:p.Thr157Lys (chr17-2036598-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001383.6(DPH1):c.470C>A(p.Thr157Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T157I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DPH1
NM_001383.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.16

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):

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

DPH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18346548).

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
DPH1	NM_001383.6	MANE Select	c.470C>A	p.Thr157Lys	missense	Exon 5 of 13	NP_001374.4
DPH1	NM_001346574.1		c.485C>A	p.Thr162Lys	missense	Exon 5 of 13	NP_001333503.1
DPH1	NM_001346575.1		c.485C>A	p.Thr162Lys	missense	Exon 5 of 13	NP_001333504.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DPH1	ENST00000263083.12	TSL:1 MANE Select	c.470C>A	p.Thr157Lys	missense	Exon 5 of 13	ENSP00000263083.7
DPH1	ENST00000575667.6	TSL:1	n.357C>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000460431.2
DPH1	ENST00000674200.2		c.485C>A	p.Thr162Lys	missense	Exon 5 of 13	ENSP00000501368.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.8

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.12

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.66

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0066

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

2.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.71

REVEL

Benign

0.085

Sift

Benign

0.74

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.42

MutPred

0.37

Gain of ubiquitination at T162 (P = 0.0289)

MVP

0.29

MPC

0.19

ClinPred

0.12

GERP RS

4.4

Varity_R

0.12

gMVP

0.61

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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