18-55461081-G-C

Position:

chr18-55461081-G-C

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Thr81Ser variant in TCF4 in gnomAD v4.1 is 0.000027 in the African population (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Thr81Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Thr81Ser variant in TCF4 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8970612/MONDO:0012589/032

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TCF4
NM_001083962.2 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:1

Conservation

PhyloP100: 4.63

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

TCF4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2 link	c.242C>G	p.Thr81Ser	missense_variant	5/20	ENST00000354452.8	NP_001077431.1	P15884-3B3KVA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8 link	c.242C>G	p.Thr81Ser	missense_variant	5/20	5	NM_001083962.2	ENSP00000346440.3		P15884-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250684

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135488

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461052

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726808

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pitt-Hopkins syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2022	This variant is present in population databases (rs760934731, gnomAD 0.008%). 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt TCF4 protein function. This variant has not been reported in the literature in individuals affected with TCF4-related conditions. This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 81 of the TCF4 protein (p.Thr81Ser). -
Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jun 25, 2024	The highest population minor allele frequency of the p.Thr81Ser variant in TCF4 in gnomAD v4.1 is 0.000027 in the African population (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Thr81Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Thr81Ser variant in TCF4 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

.;T;.;T;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;T;.;.;T;T;T;.;.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

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;D

M_CAP

Benign

0.0046

MetaRNN

Benign

0.16

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

-1.1

MutationAssessor

Benign

0.76

.;N;.;.;.;N;N;N;.;.;.;.;.;N;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.070

.;N;.;.;.;N;N;.;N;N;N;N;N;N;.;N;.;N;N;.;N;.;.;.;.;N;.;N;N;.;N;N

REVEL

Benign

0.080

Sift

Benign

0.60

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

Sift4G

Benign

0.78

T;T;.;.;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;T;T;T;.;.;T;T;T;.;.

Polyphen

0.82, 0.52

.;P;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.37

MutPred

0.10

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at S184 (P = 0.1848);.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.30

MPC

0.53

ClinPred

0.28

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.14

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

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