rs35394823

Positions:

• chr17-2040586-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001383.6(DPH1):​c.988C>G​(p.Leu330Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 1,614,084 control chromosomes in the GnomAD database, including 6,333 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.068 (508 hom., cov: 33)
  • Exomes 𝑓: 0.086 (5825 hom.)
• Consequence: DPH1 NM_001383.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026078522).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPH1	NM_001383.6	c.988C>G	p.Leu330Val	missense_variant	9/13	ENST00000263083.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPH1	ENST00000263083.12	c.988C>G	p.Leu330Val	missense_variant	9/13	1	NM_001383.6	P1

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 10398 AN: 152204 Hom.: 509 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0923

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.000960

Gnomad SAS AF: 0.0820

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.0607

GnomAD3 exomes AF: 0.0811 AC: 20232 AN: 249528 Hom.: 950 AF XY: 0.0807 AC XY: 10922 AN XY: 135400

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.0542

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0856

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0897

Gnomad OTH exome AF: 0.0841

GnomAD4 exome AF: 0.0862 AC: 125966 AN: 1461762 Hom.: 5825 Cov.: 34 AF XY: 0.0863 AC XY: 62774 AN XY: 727184

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0526

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0852

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0910

Gnomad4 OTH exome AF: 0.0754

GnomAD4 genome AF: 0.0683 AC: 10399 AN: 152322 Hom.: 508 Cov.: 33 AF XY: 0.0693 AC XY: 5160 AN XY: 74478

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.0925

Gnomad4 ASJ AF: 0.0580

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0818

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0917

Gnomad4 OTH AF: 0.0596

Alfa AF: 0.0816 Hom.: 191

Bravo AF: 0.0641

TwinsUK AF: 0.0947 AC: 351

ALSPAC AF: 0.0911 AC: 351

ESP6500AA AF: 0.0199 AC: 81

ESP6500EA AF: 0.0879 AC: 734

ExAC AF: 0.0801 AC: 9691

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.0868

EpiControl AF: 0.0816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.0000064	P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.20
Sift	Uncertain	0.016	D;.
Sift4G	Uncertain	0.030	D;T
Polyphen		0.62	P;.
Vest4		0.36
MPC		0.59
ClinPred		0.020	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.68

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

Other links and lift over

dbSNP: rs35394823; hg19: chr17-1943880;