chr18-55461054-T-C

Position:

chr18-55461054-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BA1BP4BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Asn90Ser variant in TCF4 is 1.5% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Asn90Ser variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn90Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn90Ser variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA234991/MONDO:0012589/016

Frequency

Genomes: 𝑓 0.00064 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 4 hom. )

Consequence

TCF4
NM_001083962.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 4.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

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

BS2

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

BA1

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 linkuse as main transcript	c.269A>G	p.Asn90Ser	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 linkuse as main transcript	c.269A>G	p.Asn90Ser	missense_variant	5/20	5	NM_001083962.2	ENSP00000346440.3		P15884-3

Frequencies

GnomAD3 genomes

AF:

0.000637

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000798

AC:

200

AN:

250778

Hom.:

AF XY:

0.000627

AC XY:

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000394

AC:

575

AN:

1461102

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

272

AN XY:

726830

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.0153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000864

Gnomad4 OTH exome

AF:

0.000928

GnomAD4 genome

AF:

0.000637

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000796

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000906

Hom.:

Bravo

AF:

0.000650

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000651

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 13, 2017	- -

Pitt-Hopkins syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The allele frequency of the p.Asn90Ser variant in TCF4 is 1.5% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Asn90Ser variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn90Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn90Ser variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2017

This alteration is classified as 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

TCF4: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.30

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

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.025

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.0033

MetaRNN

Benign

0.0054

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

-1.0

MutationAssessor

Benign

-0.94

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

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.23

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

REVEL

Benign

0.061

Sift

Benign

0.78

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

Sift4G

Benign

1.0

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

Polyphen

0.0010, 0.032

.;B;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.42

MVP

0.33

MPC

0.47

ClinPred

0.027

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.15

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