rs121909122

chr18-55254694-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001083962.2(TCF4):c.1153C>T(p.Arg385Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF4 NM_001083962.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.11

Genes affected

TCF4 (HGNC:11634): (transcription factor 4) This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 18-55254694-G-A is Pathogenic according to our data. Variant chr18-55254694-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-55254694-G-A is described in Lovd as [Pathogenic]. Variant chr18-55254694-G-A is described in Lovd as [Likely_pathogenic]. Variant chr18-55254694-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.1153C>T	p.Arg385Ter	stop_gained	15/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.1153C>T	p.Arg385Ter	stop_gained	15/20	5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457360 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724474

Gnomad4 AFR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pitt-Hopkins syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 04, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7372). This premature translational stop signal has been observed in individual(s) with clinical features of Pitt-Hopkins syndrome or intellectual disability (PMID: 17436255, 25356899). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg385*) in the TCF4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCF4 are known to be pathogenic (PMID: 18728071, 22045651). -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Arg487Ter variant in TCF4 was identified by our study in one individual with partial agenesis of the corpus callosum and global developmental delay. Trio exome analysis showed this variant to be de novo. The p.Arg487Ter variant in TCF4 has been previously reported in 4 unrelated individuals with Pitt-Hopkins syndrome (PMID: 32429945, PMID: 25356899, PMID: 32056211, PMID: 17436255). This variant was found to be de novo in 3 individuals with confirmed paternity and maternity (PMID: 32429945, PMID: 25356899, PMID: 17436255). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant.n This variant has also been reported in ClinVar (Variation ID: 7372) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg487Ter variant may impact protein function (PMID: 17436255). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 487, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TCF4 gene is an established disease mechanism in autosomal dominant Pitt-Hopkins syndrome. In summary, this variant meets criteria to be classified as pathogenic for Pitt-Hopkins syndrome. ACMG/AMP Criteria applied: PVS1, PS2, PS3_Supporting, PS4_Moderate, PM2_Supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Apr 26, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Pitt-Hopkins syndrome (MIM#610954). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and have been observed in individuals with Pitt-Hopkins syndrome. Where parental testing is available, these variants are usually de novo (DECIPHER, PMID: 17436255). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in patients with Pitt-Hopkins syndrome or neurodevelopmental disorder (ClinVar, PMID: 17436255, PMID: 32056211). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2023	Published functional studies demonstrate a damaging effect: impaired protein interaction (Zweier et al., 2007); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32056211, 32429945, 31440721, 32971458, 17436255, 25356899) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -

Pitt-Hopkins syndrome;C2750451:Corneal dystrophy, Fuchs endothelial, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Feb 28, 2019

[ACMG/AMP: PVS1, PS2, PS3, PM2, PS4_Moderate] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	43
Dann	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4		0.98
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs121909122; hg19: chr18-52921925;