rs35394823

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-2040586-C-A
• chr17-2040586-C-G

Variant summary

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

The NM_001383.6(DPH1):​c.988C>A​(p.Leu330Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DPH1 NM_001383.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90
• 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):

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

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, PanelApp Australia
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.988C>A	p.Leu330Ile	missense	Exon 9 of 13	NP_001374.4
	DPH1	NM_001346574.1		c.940C>A	p.Leu314Ile	missense	Exon 9 of 13	NP_001333503.1
	DPH1	NM_001346575.1		c.907C>A	p.Leu303Ile	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>A	p.Leu330Ile	missense	Exon 9 of 13	ENSP00000263083.7
	DPH1	ENST00000571710.6	TSL:1	c.115C>A	p.Leu39Ile	missense	Exon 2 of 5	ENSP00000460813.1
	DPH1	ENST00000575667.6	TSL:1	n.*233C>A		non_coding_transcript_exon	Exon 8 of 12	ENSP00000460431.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461842 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.18
Sift	Benign	0.045	D
Sift4G	Uncertain	0.054	T
Polyphen		0.42	B
Vest4		0.50
MutPred		0.54		Gain of catalytic residue at P337 (P = 0.0329)
MVP		0.54
MPC		0.61
ClinPred		0.87	D
GERP RS		5.4
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.55
Mutation Taster		=72/28	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: rs35394823; hg19: chr17-1943880;