17-2030171-T-C

Variant names:

• chr17-2030171-T-C
• rs757167361
• NM_001383.6:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001383.6(DPH1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,526 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DPH1 NM_001383.6 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.958
• Publications: 4 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 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 76 codons. Genomic position: 2033790. Lost 0.172 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.2T>C	p.Met1?	start_lost	Exon 1 of 13	NP_001374.4	Q9BZG8-4
	DPH1	NM_001346574.1		c.17T>C	p.Met6Thr	missense	Exon 1 of 13	NP_001333503.1
	DPH1	NM_001346575.1		c.17T>C	p.Met6Thr	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.2T>C	p.Met1?	start_lost	Exon 1 of 13	ENSP00000263083.7	Q9BZG8-4
	DPH1	ENST00000575667.6	TSL:1	n.11T>C		non_coding_transcript_exon	Exon 1 of 12	ENSP00000460431.2	A0A0A0MTR4
	DPH1	ENST00000571418.7	TSL:2	c.2T>C	p.Met1?	start_lost	Exon 1 of 13	ENSP00000458838.2	I3L1H5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000442 AC: 1 AN: 226020 AF XY: 0.00000812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000981

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450526 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 720348

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 43214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.00 AC: 0 AN: 83902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107758

Other (OTH) AF: 0.00 AC: 0 AN: 59918

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000834 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.96
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.10
Sift	Benign	0.36	T
Sift4G	Benign	0.60	T
Polyphen		0.60	P
Vest4		0.48
MutPred		0.35		Loss of helix (P = 0.0041)
MVP		0.52
MPC		0.55
ClinPred		0.67	D
GERP RS		4.7
PromoterAI		-0.71	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.13
gMVP		0.74
Mutation Taster		=67/33	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: rs757167361; hg19: chr17-1933465;