chr17-2030158-C-T

Variant names:

• chr17-2030158-C-T
• rs969706846
• NM_001383.6:c.-12C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001346574.1(DPH1):​c.4C>T​(p.Arg2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,449,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DPH1 NM_001346574.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.363
• Publications: 0 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
• developmental delay with short stature, dysmorphic facial features, and sparse hair 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10992193).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346574.1. 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.-12C>T		5_prime_UTR	Exon 1 of 13	NP_001374.4	Q9BZG8-4
	DPH1	NM_001346574.1		c.4C>T	p.Arg2Cys	missense	Exon 1 of 13	NP_001333503.1
	DPH1	NM_001346575.1		c.4C>T	p.Arg2Cys	missense	Exon 1 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.-12C>T		5_prime_UTR	Exon 1 of 13	ENSP00000263083.7	Q9BZG8-4
	DPH1	ENST00000674200.2		c.4C>T	p.Arg2Cys	missense	Exon 1 of 13	ENSP00000501368.1	Q9BZG8-1
	DPH1	ENST00000575667.6	TSL:1	n.-3C>T		upstream_gene	N/A	ENSP00000460431.2	A0A0A0MTR4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000222 AC: 5 AN: 224996 AF XY: 0.0000245

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000155

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1449176 Hom.: 0 Cov.: 32 AF XY: 0.00000556 AC XY: 4 AN XY: 719546

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.000140 AC: 6 AN: 42888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39264

South Asian (SAS) AF: 0.00 AC: 0 AN: 83658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107040

Other (OTH) AF: 0.00 AC: 0 AN: 59894

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.36
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.035
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.0	B
Vest4		0.18
MutPred		0.28		Loss of MoRF binding (P = 0.0784)
MVP		0.22
MPC		0.17
ClinPred		0.18	T
GERP RS		1.5
PromoterAI		-0.43	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.75
Mutation Taster		=97/3	polymorphism

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: rs969706846; hg19: chr17-1933452;