18-55228300-T-C

Position:

chr18-55228300-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001083962.2(TCF4):c.1941A>G(p.Ser647=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,613,772 control chromosomes in the GnomAD database, including 115,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10510 hom., cov: 31)

Exomes 𝑓: 0.38 ( 105288 hom. )

Consequence

TCF4
NM_001083962.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.06

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 18-55228300-T-C is Benign according to our data. Variant chr18-55228300-T-C is described in ClinVar as [Benign]. Clinvar id is 93544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-55228300-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.06 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2 linkuse as main transcript	c.1941A>G	p.Ser647=	synonymous_variant	19/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8 linkuse as main transcript	c.1941A>G	p.Ser647=	synonymous_variant	19/20	5	NM_001083962.2	P3	P15884-3

Frequencies

GnomAD3 genomes

AF:

0.371

AC:

56295

AN:

151890

Hom.:

10500

Cov.:

show subpopulations

Gnomad AFR

AF:

0.324

Gnomad AMI

AF:

0.521

Gnomad AMR

AF:

0.395

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.265

Gnomad FIN

AF:

0.394

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.387

Gnomad OTH

AF:

0.377

GnomAD3 exomes

AF:

0.375

AC:

94350

AN:

251378

Hom.:

18266

AF XY:

0.372

AC XY:

50542

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.319

Gnomad AMR exome

AF:

0.359

Gnomad ASJ exome

AF:

0.449

Gnomad EAS exome

AF:

0.444

Gnomad SAS exome

AF:

0.272

Gnomad FIN exome

AF:

0.397

Gnomad NFE exome

AF:

0.393

Gnomad OTH exome

AF:

0.398

GnomAD4 exome

AF:

0.378

AC:

552619

AN:

1461764

Hom.:

105288

Cov.:

AF XY:

0.376

AC XY:

273634

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.319

Gnomad4 AMR exome

AF:

0.365

Gnomad4 ASJ exome

AF:

0.447

Gnomad4 EAS exome

AF:

0.405

Gnomad4 SAS exome

AF:

0.272

Gnomad4 FIN exome

AF:

0.395

Gnomad4 NFE exome

AF:

0.385

Gnomad4 OTH exome

AF:

0.385

GnomAD4 genome

AF:

0.370

AC:

56315

AN:

152008

Hom.:

10510

Cov.:

AF XY:

0.370

AC XY:

27521

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.324

Gnomad4 AMR

AF:

0.395

Gnomad4 ASJ

AF:

0.430

Gnomad4 EAS

AF:

0.427

Gnomad4 SAS

AF:

0.265

Gnomad4 FIN

AF:

0.394

Gnomad4 NFE

AF:

0.387

Gnomad4 OTH

AF:

0.374

Alfa

AF:

0.392

Hom.:

3821

Bravo

AF:

0.375

Asia WGS

AF:

0.342

AC:

1191

AN:

3478

EpiCase

AF:

0.386

EpiControl

AF:

0.392

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2012	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	Eurofins Ntd Llc (ga)	Jun 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Pitt-Hopkins syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

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

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 07, 2018

- -

Corneal dystrophy, Fuchs endothelial, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.7

DANN

Benign

0.49

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