dbSNP rs1285486074: DPH1:p.Gln12Lys (chr17-2030203-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001383.6(DPH1):c.34C>A(p.Gln12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q12R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DPH1
NM_001383.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039453268).

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>A	p.Gln12Lys	missense	Exon 1 of 13	NP_001374.4	Q9BZG8-4
DPH1	NM_001346574.1		c.49C>A	p.Gln17Lys	missense	Exon 1 of 13	NP_001333503.1
DPH1	NM_001346575.1		c.49C>A	p.Gln17Lys	missense	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>A	p.Gln12Lys	missense	Exon 1 of 13	ENSP00000263083.7	Q9BZG8-4
DPH1	ENST00000575667.6	TSL:1	n.43C>A		non_coding_transcript_exon	Exon 1 of 12	ENSP00000460431.2	A0A0A0MTR4
DPH1	ENST00000674200.2		c.49C>A	p.Gln17Lys	missense	Exon 1 of 13	ENSP00000501368.1	Q9BZG8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447410

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718544

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

42654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25740

East Asian (EAS)

AF:

0.00

AC:

AN:

39198

South Asian (SAS)

AF:

0.00

AC:

AN:

83534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106350

Other (OTH)

AF:

0.00

AC:

AN:

59788

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental delay with short stature, dysmorphic facial features, and sparse hair (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.1

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.086

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.00055

LIST_S2

Benign

0.55

M_CAP

Benign

0.0023

MetaRNN

Benign

0.039

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

PhyloP100

-0.30

PrimateAI

Benign

0.36

PROVEAN

Benign

0.15

REVEL

Benign

0.040

Sift

Benign

0.89

Sift4G

Benign

0.92

Polyphen

0.0020

Vest4

0.19

MutPred

0.15

Gain of ubiquitination at Q17 (P = 0.0037)

MVP

0.27

MPC

0.16

ClinPred

0.036

GERP RS

2.7

PromoterAI

0.0061

Neutral

(source)

Varity_R

0.18

gMVP

0.56

Mutation Taster

=98/2

polymorphism

(source)

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

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