rs587784464

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 (★★). Synonymous variant affecting the same amino acid position (i.e. R157R) has been classified as Likely benign. 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:4
• 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	UniProt
TCF4	NM_001083962.2	c.469C>T	p.Arg157Ter	stop_gained	7/20	ENST00000354452.8

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 06, 2023	- -

Pitt-Hopkins syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

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;