1-26432893-T-G

Variant names:

• chr1-26432893-T-G
• rs375098683
• NM_205861.3:c.-53T>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_205861.3(DHDDS):​c.-53T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000698 in 1,590,906 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (2 hom.)
• Consequence: DHDDS NM_205861.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.231

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHDDS	NM_205861.3	c.-53T>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	ENST00000236342.12	NP_995583.1
DHDDS	NM_205861.3	c.-53T>G		splice_region_variant	Exon 2 of 9	ENST00000236342.12	NP_995583.1
DHDDS	NM_205861.3	c.-53T>G		5_prime_UTR_variant	Exon 2 of 9	ENST00000236342.12	NP_995583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHDDS	ENST00000236342	c.-53T>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	1	NM_205861.3	ENSP00000236342.7
DHDDS	ENST00000236342.12	c.-53T>G		splice_region_variant	Exon 2 of 9	1	NM_205861.3	ENSP00000236342.7
DHDDS	ENST00000236342	c.-53T>G		5_prime_UTR_variant	Exon 2 of 9	1	NM_205861.3	ENSP00000236342.7

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152226 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000728 AC: 1047 AN: 1438680 Hom.: 2 Cov.: 25 AF XY: 0.000721 AC XY: 517 AN XY: 717304

Gnomad4 AFR exome AF: 0.0000908

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000746

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.000832

Gnomad4 OTH exome AF: 0.000571

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.000444 AC XY: 33 AN XY: 74370

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000705

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000329

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.7
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

LitVar

Other links and lift over

dbSNP: rs375098683; hg19: chr1-26759384;