rs587784469

chr18-55261466-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001083962.2(TCF4):c.990G>A(p.Ser330=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 0.464

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 18-55261466-C-T is Pathogenic according to our data. Variant chr18-55261466-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 160092.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr18-55261466-C-T is described in Lovd as [Pathogenic]. Variant chr18-55261466-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.990G>A	p.Ser330=	splice_region_variant, synonymous_variant	12/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.990G>A	p.Ser330=	splice_region_variant, synonymous_variant	12/20	5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Pitt-Hopkins syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Aug 01, 2017	De novo variant at the last nucleotide position in gxon 13 of the TCF4 gene in a patient with hypotonia and developmental delay. This Variant has been previously reported as de novo (PMID22495309) in a patient with ID. In house splicing assays showed aberrant splicing. The variant is thus scored as pathogenic (ACMG class 5). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 16, 2023	Variant summary: TCF4 c.990G>A (p.Ser330Ser) alters the non-conserved last nucleotide of exon 12 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. One submitter via Clinvar stated that an in house splicing assay showed aberrant splicing, however did not provide supporting data (Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universitt Erlangen-Nrnberg). The variant was absent in 250940 control chromosomes. c.990G>A has been reported in the literature in individuals affected with Pitt-Hopkins Syndrome, autism spectrum disorder, intellectual disabilities, and neurodevelopmental disorders, including multiple affected individuals in which the variant was de novo (e.g., Geoffrey_2015, Tan_2016, Popp_2017, Mary_2018, Turner_2019, Satterstrom_2020, Martinez-Granero_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported in the literature. Three ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Feb 23, 2024	The p.Ser330= variant in TCF4 is absent from gnomAD v4 (PM2_supporting). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). The p.Ser330= variant has been observed in at least 2 individuals with intellectual disability/autism (PMIDs: 29695756, 25693842) (PS4_supporting). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with intellectual disability (PMID: 25693842, internal database -Invitae) (PM6). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in at least 3 individuals with intellectual disability/autism (PMIDs: 29695756, 29158550, 31785789, 1981491, 33767182, internal database - Invitae) (PS2_very strong). In summary, the p.Ser330= variant in TCF4 is classified as pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM2_supporting, PP3, PS4_supporting, PM6, PS2_very strong). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 19, 2023	PS4, PP3, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25693842, 29695756, 33767182, 28191890, 22495309, 25780760, 32579932, 27694994, 31785789, 29158550, 32369273, 31069529, 31981491) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TCF4: PS2, PM2:Supporting, PP3, PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	24
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784469; hg19: chr18-52928697; COSMIC: COSV61890267; COSMIC: COSV61890267;