17-2040586-C-G

Variant names:

• chr17-2040586-C-G
• rs35394823
• NM_001383.6:c.988C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 22 publications found

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
• craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet
• developmental delay with short stature, dysmorphic facial features, and sparse hair 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH1	NM_001383.6	MANE Select	c.988C>G	p.Leu330Val	missense	Exon 9 of 13	NP_001374.4	Q9BZG8-4
	DPH1	NM_001346574.1		c.940C>G	p.Leu314Val	missense	Exon 9 of 13	NP_001333503.1
	DPH1	NM_001346575.1		c.907C>G	p.Leu303Val	missense	Exon 9 of 13	NP_001333504.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH1	ENST00000263083.12	TSL:1 MANE Select	c.988C>G	p.Leu330Val	missense	Exon 9 of 13	ENSP00000263083.7	Q9BZG8-4
	DPH1	ENST00000571710.6	TSL:1	c.115C>G	p.Leu39Val	missense	Exon 2 of 5	ENSP00000460813.1	I3L3X9
	DPH1	ENST00000575667.6	TSL:1	n.*233C>G		non_coding_transcript_exon	Exon 8 of 12	ENSP00000460431.2	A0A0A0MTR4

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

GnomAD2 exomes AF: 0.0811 AC: 20232 AN: 249528 AF XY: 0.0807

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 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

African (AFR) AF: 0.0121 AC: 406 AN: 33480

American (AMR) AF: 0.104 AC: 4672 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0526 AC: 1374 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0852 AC: 7353 AN: 86256

European-Finnish (FIN) AF: 0.115 AC: 6139 AN: 53398

Middle Eastern (MID) AF: 0.0531 AC: 306 AN: 5768

European-Non Finnish (NFE) AF: 0.0910 AC: 101151 AN: 1111908

Other (OTH) AF: 0.0754 AC: 4552 AN: 60392

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

African (AFR) AF: 0.0164 AC: 682 AN: 41582

American (AMR) AF: 0.0925 AC: 1416 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 201 AN: 3468

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5194

South Asian (SAS) AF: 0.0818 AC: 395 AN: 4828

European-Finnish (FIN) AF: 0.114 AC: 1211 AN: 10602

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0917 AC: 6238 AN: 68028

Other (OTH) AF: 0.0596 AC: 126 AN: 2114

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 v4.9

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
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.030	D
Polyphen		0.62	P
Vest4		0.36
MPC		0.59
ClinPred		0.020	T
GERP RS		5.4
PromoterAI		0.0074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.68
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35394823; hg19: chr17-1943880; COSMIC: COSV107310256; COSMIC: COSV107310256;