rs587784464

Positions:

• chr18-55350904-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001083962.2(TCF4):​c.469C>T​(p.Arg157Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TCF4 NM_001083962.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.57

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-55350904-G-A is Pathogenic according to our data. Variant chr18-55350904-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 160085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-55350904-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.469C>T	p.Arg157Ter	stop_gained	7/20	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.469C>T	p.Arg157Ter	stop_gained	7/20	5	NM_001083962.2	ENSP00000346440	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pitt-Hopkins syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	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). Fuchs endothelial corneal dystrophy (MIM#613267) is only caused by expanded CTG repeats (OMIM), with the mechanism unclear. (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 (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic (ClinVar, LOVD) and observed in at least two de novo individuals with Pitt Hopkins syndrome (PMID: 22670824, PMID: 18728071). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2023	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: 18728071, 22460224, 30830316, 28807867, 24651015, 27535533, 36393831, 22670824) -

Autism spectrum disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay. The loss-of-function is a known mechanism of disease. Individuals will exhibit developmental disorders. This variant is associated with the following publications: PMID: 18728071, 22460224, 30830316, 28807867, 24651015, 27535533, 36393831, 22670824). TCF4 gene variants have been associated with neuropsychiatric diseases such as schizophrenia, bipolar disorder, intellectual disability. TCF4 gene polymorphisms are linked to autism spectrum disorder (PMID: 36448207), Pitt-Hopkins Syndrome (PMID: 17478476, 17436254, 17436255, 728011). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;D;D
Vest4		0.97, 0.97, 0.96, 0.96, 0.95, 0.96, 0.97, 0.96, 0.97, 0.98
GERP RS		4.5

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: rs587784464; hg19: chr18-53018135; COSMIC: COSV61890627; COSMIC: COSV61890627;