Menu
GeneBe

18-55234615-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001083962.2(TCF4):c.1419G>C(p.Pro473=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,066 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P473P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

TCF4
NM_001083962.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.43
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]

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=-0.86).
BP6
Variant 18-55234615-C-G is Benign according to our data. Variant chr18-55234615-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 93541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-55234615-C-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-4.43 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00217 (330/152182) while in subpopulation NFE AF= 0.00273 (186/68008). AF 95% confidence interval is 0.00241. There are 3 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd at 330 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TCF4NM_001083962.2 linkuse as main transcriptc.1419G>C p.Pro473= synonymous_variant 16/20 ENST00000354452.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TCF4ENST00000354452.8 linkuse as main transcriptc.1419G>C p.Pro473= synonymous_variant 16/205 NM_001083962.2 P3P15884-3

Frequencies

GnomAD3 genomes
AF:
0.00217
AC:
330
AN:
152064
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00548
Gnomad AMR
AF:
0.00177
Gnomad ASJ
AF:
0.0228
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00273
Gnomad OTH
AF:
0.00382
GnomAD3 exomes
AF:
0.00226
AC:
567
AN:
251412
Hom.:
2
AF XY:
0.00216
AC XY:
293
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.000738
Gnomad AMR exome
AF:
0.00150
Gnomad ASJ exome
AF:
0.0179
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.00267
Gnomad OTH exome
AF:
0.00261
GnomAD4 exome
AF:
0.00252
AC:
3688
AN:
1461884
Hom.:
9
Cov.:
31
AF XY:
0.00249
AC XY:
1813
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.000568
Gnomad4 AMR exome
AF:
0.00132
Gnomad4 ASJ exome
AF:
0.0180
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000356
Gnomad4 NFE exome
AF:
0.00264
Gnomad4 OTH exome
AF:
0.00291
GnomAD4 genome
AF:
0.00217
AC:
330
AN:
152182
Hom.:
3
Cov.:
32
AF XY:
0.00206
AC XY:
153
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.000554
Gnomad4 AMR
AF:
0.00177
Gnomad4 ASJ
AF:
0.0228
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.00273
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.00374
Hom.:
2
Bravo
AF:
0.00238
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00333
EpiControl
AF:
0.00308

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 12, 2015- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsDec 15, 2020- -
Benign, criteria provided, single submitterclinical testingGeneDxDec 26, 2013This 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 10, 2015- -
Pitt-Hopkins syndrome Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 16, 2016This 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. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024TCF4: BP4, BP7, BS1 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
Cadd
Benign
0.39
Dann
Benign
0.63

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.

Other links and lift over

dbSNP: rs143944746; hg19: chr18-52901846; COSMIC: COSV100611312; API