rs1555796785

Positions:

• chr18-55275649-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4 PM6_Strong PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Ser253Arg variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt–Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PM6_Strong). The p.Ser253Arg variant has been observed in 3 other individuals with Pitt-Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PS4_Moderate). The p.Ser253Arg variant in TCF4 is absent from gnomAD (PM2_Supporting). The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt–Hopkins syndrome (PMID 26993267, described as p.Ser355Arg) (PP4). In summary, the p.Ser253Arg variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM2_supporting, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA402701458/MONDO:0012589/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 3.71

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 Likely_pathogenic. Variant got 8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.759C>G	p.Ser253Arg	missense_variant	10/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.759C>G	p.Ser253Arg	missense_variant	10/20	5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Pitt-Hopkins syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The p.Ser253Arg variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PM6_Strong). The p.Ser253Arg variant has been observed in 3 other individuals with Pitt-Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PS4_Moderate). The p.Ser253Arg variant in TCF4 is absent from gnomAD (PM2_Supporting). The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt-Hopkins syndrome (PMID 26993267, described as p.Ser355Arg) (PP4). In summary, the p.Ser253Arg variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM2_supporting, PP4). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 05, 2016	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2016

The S253R variant in the TCF4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S253R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S253R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, splice predictor models show that c.759 C>G (S253R) creates a cryptic donor splice site in exon 10, which may result in abnormal gene splicing. We interpret S253R as a strong candidate for a pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	.;T;D;.;T;T;T;.;.;D;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;T;T;.;T;.;T;.;.;T;.;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;.;.;.;D;D;D;D;D;D;.;D;.;D;D;D;D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.;.;.;.;M;M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	.;.;D;.;.;.;.;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;N;D;.;D;D;D;.;.;.;.;.;.;N;.;D;D;.;.;D;.;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.0060	.;.;D;.;.;.;.;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;T;D;.;D;D;D;.;.;.;.;.;.;D;.;D;D;.;.;D;.;.;.
Sift4G	Benign	0.095	T;.;T;.;.;.;.;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;.;.;.;.;.;D;.;.;D;.;.
Polyphen		1.0, 0.98	.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.26		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of phosphorylation at S355 (P = 0.0545);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.41
MPC		2.4
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.47
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 1
DS_DL_spliceai		0.76		Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555796785; hg19: chr18-52942880;