1-100995147-T-C

Position:

• chr1-100995147-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_015958.3(DPH5):​c.493A>G​(p.Ile165Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPH5 NM_015958.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39

Genes affected

DPH5 (HGNC:24270): (diphthamide biosynthesis 5) This gene encodes a component of the diphthamide synthesis pathway. Diphthamide is a post-translationally modified histidine residue found only on translation elongation factor 2. It is conserved from archaebacteria to humans, and is targeted by diphtheria toxin and Pseudomonas exotoxin A to halt cellular protein synthesis. The yeast and Chinese hamster homologs of this protein catalyze the trimethylation of the histidine residue on elongation factor 2, resulting in a diphthine moiety that is subsequently amidated to yield diphthamide. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DPH5 (HGNC:):

SLC30A7 (HGNC:19306): (solute carrier family 30 member 7) Zinc functions as a cofactor for numerous enzymes, nuclear factors, and hormones and as an intra- and intercellular signal ion. Members of the zinc transporter (ZNT)/SLC30 subfamily of the cation diffusion facilitator family, such as SLC30A7, permit cellular efflux of zinc (Seve et al., 2004 [PubMed 15154973]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Diphthine methyl ester synthase (size 284) in uniprot entity DPH5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_015958.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPH5	NM_015958.3	c.493A>G	p.Ile165Val	missense_variant, splice_region_variant	6/8	ENST00000370109.8	NP_057042.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPH5	ENST00000370109.8	c.493A>G	p.Ile165Val	missense_variant, splice_region_variant	6/8	1	NM_015958.3	ENSP00000359127.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2024

The c.493A>G (p.I165V) alteration is located in exon 6 (coding exon 5) of the DPH5 gene. This alteration results from a A to G substitution at nucleotide position 493, causing the isoleucine (I) at amino acid position 165 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Pathogenic	3.8	H;H;H
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.98	N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.49
MutPred		0.74		Gain of methylation at K166 (P = 0.0774);Gain of methylation at K166 (P = 0.0774);Gain of methylation at K166 (P = 0.0774);
MVP		0.52
MPC		0.33
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-101460703;