19-12675855-C-T

Variant names:

• chr19-12675855-C-T
• rs375107894
• NM_001930.4:c.1093G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001930.4(DHPS):​c.1093G>A​(p.Glu365Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DHPS NM_001930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2162002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHPS	NM_001930.4	c.1093G>A	p.Glu365Lys	missense_variant	Exon 9 of 9	ENST00000210060.12	NP_001921.1
WDR83	NM_001099737.3	c.*183C>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.1093G>A	p.Glu365Lys	missense_variant	Exon 9 of 9	1	NM_001930.4	ENSP00000210060.6
ENSG00000285589	ENST00000648033.1	n.*638G>A		non_coding_transcript_exon_variant	Exon 9 of 14			ENSP00000498000.1
ENSG00000285589	ENST00000648033.1	n.*638G>A		3_prime_UTR_variant	Exon 9 of 14			ENSP00000498000.1
WDR83	ENST00000418543.8	c.*183C>T		downstream_gene_variant		1	NM_001099737.3	ENSP00000402653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452980 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722348

Gnomad4 AFR exome AF: 0.0000302

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: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1093G>A (p.E365K) alteration is located in exon 9 (coding exon 9) of the DHPS gene. This alteration results from a G to A substitution at nucleotide position 1093, causing the glutamic acid (E) at amino acid position 365 to be replaced by a lysine (K). 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	0.066
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T;T;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.72	N;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.33	N;.;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.20	T;.;T;.;.
Sift4G	Benign	0.44	T;T;T;T;T
Polyphen		0.0020	B;.;B;.;.
Vest4		0.24
MutPred		0.34		Gain of ubiquitination at E365 (P = 0.0075);.;.;.;.;
MVP		0.35
MPC		0.19
ClinPred		0.60	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375107894; hg19: chr19-12786669;