Genetic Variant NM_206831.3:c.53A>G (chr3-16264824-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_206831.3(DPH3):c.53A>G(p.Asp18Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DPH3
NM_206831.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.46

Variant links:

Genes affected

DPH3 (HGNC:27717): (diphthamide biosynthesis 3) This gene encodes a CSL zinc finger-containing protein that is required for dipthamide biosynthesis. The encoded protein is necessary for the initial step in the modification of a histidine residue in elongation factor-2 to diphthamide. This modified residue is a target for ADP ribosylation by the bacterial toxins diphtheria toxin and Pseudomonas exotoxin A. Alternative splicing results in multiple transcript variants that encode the same isoform. [provided by RefSeq, Feb 2009]

DPH3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2794969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPH3	NM_206831.3 link	c.53A>G	p.Asp18Gly	missense_variant	Exon 1 of 3	ENST00000488423.2	NP_996662.1	Q96FX2-1
DPH3	NM_001047434.3 link	c.53A>G	p.Asp18Gly	missense_variant	Exon 1 of 2		NP_001040899.1	Q96FX2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DPH3	ENST00000488423.2 link	c.53A>G	p.Asp18Gly	missense_variant	Exon 1 of 3	1	NM_206831.3	ENSP00000419599.1	Q96FX2-1
DPH3	ENST00000383775.4 link	c.53A>G	p.Asp18Gly	missense_variant	Exon 1 of 2	2		ENSP00000373285.4	Q96FX2-2
DPH3	ENST00000285082.8 link	n.-47A>G		upstream_gene_variant		1
DPH3	ENST00000462982.1 link	n.-237A>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.53A>G (p.D18G) alteration is located in exon 1 (coding exon 1) of the DPH3 gene. This alteration results from a A to G substitution at nucleotide position 53, causing the aspartic acid (D) at amino acid position 18 to be replaced by a glycine (G). 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

Benign

0.18

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.60

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Benign

0.18

Sift

Benign

0.093

T;D

Sift4G

Uncertain

0.053

T;T

Polyphen

0.30

B;P

Vest4

0.39

MutPred

0.42

Gain of catalytic residue at D18 (P = 0.0808);Gain of catalytic residue at D18 (P = 0.0808);

MVP

0.56

MPC

0.18

ClinPred

1.0

GERP RS

5.2

Varity_R

0.61

gMVP

0.42

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over