rs113994102

chr18-79710825-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_004715.5(CTDP1):c.863+389C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: CTDP1 NM_004715.5 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: -1.29

Genes affected

CTDP1 (HGNC:2498): (CTD phosphatase subunit 1) This gene encodes a protein which interacts with the carboxy-terminus of the RAP74 subunit of transcription initiation factor TFIIF, and functions as a phosphatase that processively dephosphorylates the C-terminus of POLR2A (a subunit of RNA polymerase II), making it available for initiation of gene expression. Mutations in this gene are associated with congenital cataracts, facial dysmorphism and neuropathy syndrome (CCFDN). Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 18-79710825-C-T is Pathogenic according to our data. Variant chr18-79710825-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-79710825-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTDP1	NM_004715.5	c.863+389C>T		intron_variant		ENST00000613122.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTDP1	ENST00000613122.5	c.863+389C>T		intron_variant		1	NM_004715.5	P1
CTDP1	ENST00000075430.11	c.863+389C>T		intron_variant		1
CTDP1	ENST00000591598.5	c.659+389C>T		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 26

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 27, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 14517542). ClinVar contains an entry for this variant (Variation ID: 5301). This variant has been observed in individual(s) with congenital cataracts, facial dysmorphism, and neuropathy (PMID: 14517542, 23408394, 24690360, 29174527). It is commonly reported in individuals of Romani ancestry (PMID: 24690360, 29174527). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the CTDP1 gene. It does not directly change the encoded amino acid sequence of the CTDP1 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CTDP1: PM3:Very Strong, PM2, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Congenital cataracts-facial dysmorphism-neuropathy syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	4.7
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs113994102; hg19: chr18-77470825;