1-26432989-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_205861.3(DHDDS):c.44T>A(p.Phe15Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F15F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DHDDS NM_205861.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.47

Genes affected

DHDDS (HGNC:20603): (dehydrodolichyl diphosphate synthase subunit) The protein encoded by this gene catalyzes cis-prenyl chain elongation to produce the polyprenyl backbone of dolichol, a glycosyl carrier lipid required for the biosynthesis of several classes of glycoproteins. Mutations in this gene are associated with retinitis pigmentosa type 59. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

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=0.35156643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHDDS	NM_205861.3	c.44T>A	p.Phe15Tyr	missense_variant	2/9	ENST00000236342.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHDDS	ENST00000236342.12	c.44T>A	p.Phe15Tyr	missense_variant	2/9	1	NM_205861.3	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 59 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 19, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 15 of the DHDDS protein (p.Phe15Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DHDDS-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	26
Dann	Benign	0.97
DEOGEN2	Benign	0.26	T;.;T;.;.;.;T;T;.;T;T;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.13	T;D;T;D;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.82, 0.89, 0.89	.;.;P;P;.;P;.;.;.;.;.;.;.;.
Vest4		0.38
MutPred		0.41		Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);Gain of catalytic residue at F15 (P = 0.2129);
MVP		0.18
MPC		0.82
ClinPred		0.81	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.52

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: chr1-26759480;