chr17-2033516-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001346576.2(DPH1):​c.-211C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

DPH1
NM_001346576.2 5_prime_UTR_premature_start_codon_gain

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.84
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DPH1NM_001383.6 linkc.73C>T p.Arg25Trp missense_variant Exon 2 of 13 ENST00000263083.12 NP_001374.4 Q9BZG8-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DPH1ENST00000263083.12 linkc.73C>T p.Arg25Trp missense_variant Exon 2 of 13 1 NM_001383.6 ENSP00000263083.7 Q9BZG8-4

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000401
AC:
10
AN:
249178
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135346
show subpopulations
Gnomad AFR exome
AF:
0.000389
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461752
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000563
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000986
AC:
15
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.000338
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000165
Hom.:
0
Bravo
AF:
0.000144
ESP6500AA
AF:
0.000816
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000580
AC:
7
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 08, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.88C>T (p.R30W) alteration is located in exon 2 (coding exon 2) of the DPH1 gene. This alteration results from a C to T substitution at nucleotide position 88, causing the arginine (R) at amino acid position 30 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.41
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.31
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.046
D
MetaRNN
Uncertain
0.48
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.8
M
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-3.1
D
REVEL
Benign
0.092
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
0.0020
B
Vest4
0.58
MVP
0.51
MPC
0.59
ClinPred
0.63
D
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.17
gMVP
0.71

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs367898997; hg19: chr17-1936810; COSMIC: COSV53985657; COSMIC: COSV53985657; API