Variant 18-55403486-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP6_Moderate

The NM_001083962.2(TCF4):c.337G>C(p.Gly113Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TCF4
NM_001083962.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 5.52

Variant links:

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 links:

TCF4 (HGNC:):

TCF4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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.

BP6

Variant 18-55403486-C-G is Benign according to our data. Variant chr18-55403486-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 468958.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2 linkuse as main transcript	c.337G>C	p.Gly113Arg	missense_variant	6/20	ENST00000354452.8	NP_001077431.1	P15884-3B3KVA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8 linkuse as main transcript	c.337G>C	p.Gly113Arg	missense_variant	6/20	5	NM_001083962.2	ENSP00000346440.3		P15884-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Esophageal atresia;C0034194:Pyloric stenosis

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Clinical Genetics, Erasmus University Medical Center

May 22, 2019

- -

Pitt-Hopkins syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 22, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

.;D;.;T;.;D;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;T;.;T;.;.;T;.;.;T;T;T;.;.;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

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

Uncertain

0.20

MetaRNN

Uncertain

0.62

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

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.3

.;M;.;.;.;M;M;M;.;.;.;.;.;.;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.7

.;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.;D;.;.;.;.;D;.;D;D;.;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

.;D;.;.;.;D;D;.;D;D;D;D;D;D;D;T;.;T;.;D;D;.;.;.;D;.;.;.;.;D;.;D;D;.;D;D

Sift4G

Benign

0.099

T;D;.;.;.;D;D;D;D;D;D;D;D;D;D;T;D;T;T;D;D;.;.;.;.;.;D;D;D;.;.;D;D;D;.;.

Polyphen

0.98, 1.0

.;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.75

MutPred

0.17

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0161);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.90

MPC

1.6

ClinPred

0.99

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over