chr18-55461024-A-T

Position:

• chr18-55461024-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001083962.2(TCF4):​c.299T>A​(p.Ile100Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 7.11

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]

TCF4-AS1 (HGNC:51642): (TCF4 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• 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). GenCC has associacion of gene with intellectual disability, corneal dystrophy, Fuchs endothelial, 3, autosomal dominant non-syndromic intellectual disability, autism spectrum disorder, Fuchs' endothelial dystrophy, Pitt-Hopkins syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.299T>A	p.Ile100Lys	missense_variant	5/20	ENST00000354452.8	NP_001077431.1
TCF4-AS1	NR_132985.1	n.178+8314A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.299T>A	p.Ile100Lys	missense_variant	5/20	5	NM_001083962.2	ENSP00000346440	P3
TCF4-AS1	ENST00000587660.1	n.178+8314A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jun 18, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TCF4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with TCF4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 100 of the TCF4 protein (p.Ile100Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.89	.;D;.;T;.;D;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;T;.;.;T;T;T;.;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	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	0.032	D
MetaRNN	Uncertain	0.49	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	-0.90	T
MutationAssessor	Benign	1.6	.;L;.;.;.;L;L;L;.;.;.;.;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	.;D;.;.;.;D;D;.;D;D;D;D;D;N;.;N;.;D;D;.;D;.;.;.;.;D;.;D;D;.;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	.;D;.;.;.;D;D;.;D;D;D;D;D;D;.;D;.;D;D;.;D;.;.;.;.;D;.;D;D;.;D;D
Sift4G	Benign	0.23	T;D;.;.;.;D;D;D;D;D;D;D;D;T;D;T;T;D;D;.;.;.;D;D;D;.;.;D;D;D;.;.
Polyphen		0.83, 0.96	.;P;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.76
MutPred		0.26		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of methylation at I202 (P = 0.0179);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		1.1
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.39
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-53128255;