chr18-55228895-G-T

Position:

• chr18-55228895-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001083962.2(TCF4):​c.1831C>A​(p.Leu611Ile) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

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 9 ACMG points.

• PM1: In a domain bHLH (size 53) in uniprot entity ITF2_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_001083962.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TCF4. . Gene score misZ: 4.1035 (greater than the threshold 3.09). Trascript score misZ: 4.5676 (greater than threshold 3.09). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. GenCC has associacion of the gene with intellectual disability, corneal dystrophy, Fuchs endothelial, 3, autosomal dominant non-syndromic intellectual disability, autism spectrum disorder, Fuchs' endothelial dystrophy, Pitt-Hopkins syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.1831C>A	p.Leu611Ile	missense_variant	18/20	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.1831C>A	p.Leu611Ile	missense_variant	18/20	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2016

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 leucine with isoleucine at codon 611 of the TCF4 protein (p.Leu611Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;D;.;T;T;T;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	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	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.97	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
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	.;.;H;.;.;.;.;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.9	.;.;N;.;.;.;.;.;N;N;N;.;N;N;N;N;N;N;.;N;N;N;N;N;N;.;N;N;N;N;N;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	.;.;D;.;.;.;.;.;D;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;D;.;D;T;D;D;D;.
Sift4G	Pathogenic	0.0	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
Polyphen		0.98, 1.0	.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.78
MutPred		0.89		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of methylation at K709 (P = 0.0446);.;.;
MVP		0.80
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.94

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: rs1555710107; hg19: chr18-52896126;