chr17-2030204-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001383.6(DPH1):ā€‹c.35A>Gā€‹(p.Gln12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,598,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00040 ( 0 hom., cov: 32)
Exomes š‘“: 0.000035 ( 0 hom. )

Consequence

DPH1
NM_001383.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.838
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0052072406).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DPH1NM_001383.6 linkuse as main transcriptc.35A>G p.Gln12Arg missense_variant 1/13 ENST00000263083.12 NP_001374.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DPH1ENST00000263083.12 linkuse as main transcriptc.35A>G p.Gln12Arg missense_variant 1/131 NM_001383.6 ENSP00000263083 P1Q9BZG8-4

Frequencies

GnomAD3 genomes
AF:
0.000394
AC:
60
AN:
152282
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00137
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000920
AC:
20
AN:
217336
Hom.:
0
AF XY:
0.0000761
AC XY:
9
AN XY:
118276
show subpopulations
Gnomad AFR exome
AF:
0.00144
Gnomad AMR exome
AF:
0.0000319
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000103
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000353
AC:
51
AN:
1445760
Hom.:
0
Cov.:
32
AF XY:
0.0000293
AC XY:
21
AN XY:
717564
show subpopulations
Gnomad4 AFR exome
AF:
0.00111
Gnomad4 AMR exome
AF:
0.0000708
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.05e-7
Gnomad4 OTH exome
AF:
0.000151
GnomAD4 genome
AF:
0.000400
AC:
61
AN:
152400
Hom.:
0
Cov.:
32
AF XY:
0.000403
AC XY:
30
AN XY:
74530
show subpopulations
Gnomad4 AFR
AF:
0.00139
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000508
Hom.:
0
Bravo
AF:
0.000468
ESP6500AA
AF:
0.00150
AC:
6
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000117
AC:
14

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 05, 2024The c.50A>G (p.Q17R) alteration is located in exon 1 (coding exon 1) of the DPH1 gene. This alteration results from a A to G substitution at nucleotide position 50, causing the glutamine (Q) at amino acid position 17 to be replaced by an arginine (R). 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
0.059
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
17
DANN
Benign
0.91
DEOGEN2
Benign
0.090
T
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.00034
N
LIST_S2
Benign
0.39
T
M_CAP
Benign
0.0031
T
MetaRNN
Benign
0.0052
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.15
N
REVEL
Benign
0.038
Sift
Benign
0.49
T
Sift4G
Benign
0.52
T
Polyphen
0.0090
B
Vest4
0.15
MVP
0.27
MPC
0.14
ClinPred
0.0085
T
GERP RS
2.7
Varity_R
0.052
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs375040102; hg19: chr17-1933498; API