rs116911386

chr17-2036598-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001383.6(DPH1):c.470C>T(p.Thr157Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,614,134 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (51 hom.)
• Consequence: DPH1 NM_001383.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.16

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010593861).
• BP6: Variant 17-2036598-C-T is Benign according to our data. Variant chr17-2036598-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00573 (872/152312) while in subpopulation NFE AF= 0.00889 (605/68024). AF 95% confidence interval is 0.00831. There are 0 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPH1	NM_001383.6	c.470C>T	p.Thr157Ile	missense_variant	5/13	ENST00000263083.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPH1	ENST00000263083.12	c.470C>T	p.Thr157Ile	missense_variant	5/13	1	NM_001383.6	P1

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00889

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00596 AC: 1486 AN: 249438 Hom.: 7 AF XY: 0.00617 AC XY: 835 AN XY: 135368

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00374

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00834

Gnomad OTH exome AF: 0.00743

GnomAD4 exome AF: 0.00672 AC: 9827 AN: 1461822 Hom.: 51 Cov.: 31 AF XY: 0.00671 AC XY: 4883 AN XY: 727212

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00451

Gnomad4 FIN exome AF: 0.00253

Gnomad4 NFE exome AF: 0.00740

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.00573 AC: 872 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74464

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00889

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00855 Hom.: 5

Bravo AF: 0.00552

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00118 AC: 5

ESP6500EA AF: 0.00994 AC: 84

ExAC AF: 0.00608 AC: 736

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0114

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DPH1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.74	N;.
REVEL	Benign	0.038
Sift	Benign	0.16	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.0010	B;.
Vest4		0.35
MVP		0.40
MPC		0.15
ClinPred		0.0089	T
GERP RS		4.4
Varity_R		0.059
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs116911386; hg19: chr17-1939892; COSMIC: COSV99559516; COSMIC: COSV99559516;