19-12676078-C-T

Variant names:

• chr19-12676078-C-T
• rs888951095
• NM_001930.4:c.953G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001930.4(DHPS):​c.953G>A​(p.Gly318Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHPS NM_001930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

Genes affected

DHPS (HGNC:2869): (deoxyhypusine synthase) This gene encodes a protein that is required for the formation of hypusine, a unique amino acid formed by the posttranslational modification of only one protein, eukaryotic translation initiation factor 5A. The encoded protein catalyzes the first step in hypusine formation by transferring the butylamine moiety of spermidine to a specific lysine residue of the eukaryotic translation initiation factor 5A precursor, forming an intermediate deoxyhypusine residue. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2011]

ENSG00000285589 (HGNC:):

WDR83 (HGNC:32672): (WD repeat domain 83) This gene encodes a member of the WD-40 protein family. The protein is proposed to function as a molecular scaffold for various multimeric protein complexes. The protein associates with several components of the extracellular signal-regulated kinase (ERK) pathway, and promotes ERK activity in response to serum or other signals. The protein also interacts with egl nine homolog 3 (EGLN3, also known as PHD3) and regulates expression of hypoxia-inducible factor 1, and has been purified as part of the spliceosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHPS	NM_001930.4	c.953G>A	p.Gly318Asp	missense_variant	Exon 8 of 9	ENST00000210060.12	NP_001921.1
WDR83	NM_001099737.3	c.*406C>T		downstream_gene_variant		ENST00000418543.8	NP_001093207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHPS	ENST00000210060.12	c.953G>A	p.Gly318Asp	missense_variant	Exon 8 of 9	1	NM_001930.4	ENSP00000210060.6
ENSG00000285589	ENST00000648033.1	n.*498G>A		non_coding_transcript_exon_variant	Exon 8 of 14			ENSP00000498000.1
ENSG00000285589	ENST00000648033.1	n.*498G>A		3_prime_UTR_variant	Exon 8 of 14			ENSP00000498000.1
WDR83	ENST00000418543.8	c.*406C>T		downstream_gene_variant		1	NM_001099737.3	ENSP00000402653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.953G>A (p.G318D) alteration is located in exon 8 (coding exon 8) of the DHPS gene. This alteration results from a G to A substitution at nucleotide position 953, causing the glycine (G) at amino acid position 318 to be replaced by an aspartic acid (D). 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	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;T;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;T;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.7	D;.;D;.;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.93
MutPred		0.93		Loss of catalytic residue at G318 (P = 0.065);.;.;.;.;
MVP		0.99
MPC		0.79
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs888951095; hg19: chr19-12786892;