rs200530055

Variant names:

• chr17-2036050-T-C
• rs200530055
• NM_001383.6:c.359T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3 PP5

The NM_001383.6(DPH1):​c.359T>C​(p.Leu120Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000496 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002521569: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:30877278)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: DPH1 NM_001383.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 6.00
• 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 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002521569: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 30877278).; SCV001801109: Published functional studies demonstrate a damaging effect of reduced ADP-ribosylated eEF2 (PMID: 30877278); SCV004738833: Functional studies of DPH1 p.Leu125Pro showed reduced enzyme activity (Urreizti et al. 2020. PubMed ID: 30877278).; SCV005062081: At least one publication reports experimental evidence evaluating an impact on protein function demonstrating reduced amounts of ADP-ribosylated eEF2 (Urreizti_2020). PMID: 32732226, 30877278
• PP5: Variant 17-2036050-T-C is Pathogenic according to our data. Variant chr17-2036050-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521028.

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.359T>C	p.Leu120Pro	missense	Exon 4 of 13	NP_001374.4	Q9BZG8-4
	DPH1	NM_001346574.1		c.374T>C	p.Leu125Pro	missense	Exon 4 of 13	NP_001333503.1
	DPH1	NM_001346575.1		c.374T>C	p.Leu125Pro	missense	Exon 4 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.359T>C	p.Leu120Pro	missense	Exon 4 of 13	ENSP00000263083.7	Q9BZG8-4
	DPH1	ENST00000575667.6	TSL:1	n.288-479T>C		intron	N/A	ENSP00000460431.2	A0A0A0MTR4
	DPH1	ENST00000674200.2		c.374T>C	p.Leu125Pro	missense	Exon 4 of 13	ENSP00000501368.1	Q9BZG8-1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000289 AC: 72 AN: 248874 AF XY: 0.000333

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000426

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000517 AC: 756 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.000495 AC XY: 360 AN XY: 727186

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000761 AC: 34 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000614 AC: 683 AN: 1111930

Other (OTH) AF: 0.000530 AC: 32 AN: 60384

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74434

African (AFR) AF: 0.000144 AC: 6 AN: 41542

American (AMR) AF: 0.000785 AC: 12 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.000382

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000818

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Developmental delay with short stature, dysmorphic facial features, and sparse hair (5)
3	-	-	Developmental delay with short stature, dysmorphic facial features, and sparse hair 1 (3)
1	-	-	DPH1-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.82
MPC		0.75
ClinPred		0.48	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.95
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200530055; hg19: chr17-1939344;