rs1131691735

Positions:

• chr18-55228850-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.1876C>T​(p.Arg626Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.98

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 18-55228850-G-A is Pathogenic according to our data. Variant chr18-55228850-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-55228850-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.1876C>T	p.Arg626Ter	stop_gained	18/20	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.1876C>T	p.Arg626Ter	stop_gained	18/20	5	NM_001083962.2	ENSP00000346440	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pitt-Hopkins syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 23, 2020	A heterozygous nonsense variation in exon 19 of the TCF4 gene that results in a stop codon and premature truncation of the protein at codon 728 was detected. The observed variant c.2182C>T (p.Arg728Ter) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. Segregation analysis showed this variant to be de novo. In summary, the variant meets our criteria to be classified as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Apr 05, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 30, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430016). This premature translational stop signal has been observed in individual(s) with Pitt–Hopkins Syndrome (PMID: 22045651). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg626*) 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). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	Not observed in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 46 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 22045651, 22460224, 29604340, 31440721) -
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	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The c.1876C>T (p.R626*) alteration, located in exon 18 (coding exon 17) of the TCF4 gene, consists of a C to T substitution at nucleotide position 1876. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 626. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals with clinical features of Pitt-Hopkins syndrome (Liu, 2018; Whalen, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	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		0.94
GERP RS		5.7

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: rs1131691735; hg19: chr18-52896081; COSMIC: COSV61897774;