rs757167361

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-2030171-T-A
• chr17-2030171-T-C
• chr17-2030171-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001383.6(DPH1):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPH1 NM_001383.6 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• 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):

• 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 5 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
• PP5: Variant 17-2030171-T-A is Pathogenic according to our data. Variant chr17-2030171-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 218949.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH1	NM_001383.6	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 13	NP_001374.4
	DPH1	NM_001346574.1		c.17T>A	p.Met6Lys	missense	Exon 1 of 13	NP_001333503.1
	DPH1	NM_001346575.1		c.17T>A	p.Met6Lys	missense	Exon 1 of 13	NP_001333504.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH1	ENST00000263083.12	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 13	ENSP00000263083.7
	DPH1	ENST00000575667.6	TSL:1	n.11T>A		non_coding_transcript_exon	Exon 1 of 12	ENSP00000460431.2
	DPH1	ENST00000571418.7	TSL:2	c.2T>A	p.Met1?	start_lost	Exon 1 of 13	ENSP00000458838.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental delay with short stature, dysmorphic facial features, and sparse hair 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.062
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.96
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.15
Sift	Benign	0.21	T
Sift4G	Benign	0.65	T
Polyphen		0.60	P
Vest4		0.76
MutPred		0.37		Gain of sheet (P = 0.0061)
MVP		0.53
MPC		0.68
ClinPred		0.82	D
GERP RS		4.7
PromoterAI		-0.85	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.44
gMVP		0.84
Mutation Taster		=39/61	disease causing (ClinVar)

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;