rs1555722023

chr18-55234565-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PP2 PP5_Moderate BP4

The NM_001083962.2(TCF4):c.1469C>G(p.Pro490Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P490S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.45

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 6 ACMG points.

• PM1: In a region_of_interest Disordered (size 104) in uniprot entity ITF2_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_001083962.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TCF4
• PP5: Variant 18-55234565-G-C is Pathogenic according to our data. Variant chr18-55234565-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468947.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25764036).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.1469C>G	p.Pro490Arg	missense_variant	16/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.1469C>G	p.Pro490Arg	missense_variant	16/20	5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 05, 2020

In summary, this variant is a novel de novo missense change observed in an affected individual which suggests it is pathogenic, however, in the absence of functional data, it has been classified as Likely Pathogenic.. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Family studies indicate this variant likely was not inherited from either parent (i.e. occurred de novo) in an individual with disease (Invitae database). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TCF4-related disease. This sequence change replaces proline with arginine at codon 490 of the TCF4 protein (p.Pro490Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	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	0.011	T
MetaRNN	Benign	0.26	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	-1.2	T
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	0.69	T
Sift4G	Benign	0.084	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
Polyphen		0.61, 0.93	.;.;P;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.
Vest4		0.31
MutPred		0.15		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of catalytic residue at P591 (P = 0.0393);.;.;
MVP		0.43
MPC		2.0
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.11
gMVP		0.52

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: rs1555722023; hg19: chr18-52901796;