1-43970973-G-C

Position:

• chr1-43970973-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001319171.2(DPH2):​c.-208G>C variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DPH2 NM_001319171.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75

Genes affected

DPH2 (HGNC:3004): (diphthamide biosynthesis 2) This gene is one of two human genes similar to the yeast gene dph2. The yeast gene was identified by its ability to complement a diphthamide mutant strain, and thus probably functions in diphthamide biosynthesis. Diphthamide is a post-translationally modified histidine residue present in elongation factor 2 (EF2) that is the target of diphtheria toxin ADP-ribosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ENSG00000285649 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPH2	NM_001384.5	c.268G>C	p.Val90Leu	missense_variant	3/6	ENST00000255108.8	NP_001375.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPH2	ENST00000255108.8	c.268G>C	p.Val90Leu	missense_variant	3/6	1	NM_001384.5	ENSP00000255108.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424700 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 705272

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 08, 2024

The c.268G>C (p.V90L) alteration is located in exon 3 (coding exon 3) of the DPH2 gene. This alteration results from a G to C substitution at nucleotide position 268, causing the valine (V) at amino acid position 90 to be replaced by a leucine (L). 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	0.25
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.25	B;.
Vest4		0.40
MutPred		0.52		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.64
MPC		0.57
ClinPred		0.97	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.89

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: chr1-44436645;