rs796053413

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

This summary comes from the ClinGen Evidence Repository: The p.Ser102Asn variant in TCF4 is present in 1 XX individual in gnomAD v4.0 (0.00016%) (not sufficient to meet BS1 criteria). The p.Ser102Asn variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Ser102Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ser102Asn variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA319094/MONDO:0012589/032

Frequency

Genomes: not found (cov: 32)
Exomes đť‘“: 6.8e-7 ( 0 hom. )

Consequence

TCF4
NM_001083962.2 missense, splice_region

Scores

5
12
Splicing: ADA: 0.9978
2

Clinical Significance

Likely benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 5.56
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCF4NM_001083962.2 linkc.305G>A p.Ser102Asn missense_variant, splice_region_variant Exon 6 of 20 ENST00000354452.8 NP_001077431.1 P15884-3B3KVA4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCF4ENST00000354452.8 linkc.305G>A p.Ser102Asn missense_variant, splice_region_variant Exon 6 of 20 5 NM_001083962.2 ENSP00000346440.3 P15884-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461578
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727098
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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
Cov.:
32

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Pitt-Hopkins syndrome Uncertain:1Benign:1
Likely benign, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelJun 25, 2024The p.Ser102Asn variant in TCF4 is present in 1 XX individual in gnomAD v4.0 (0.00016%) (not sufficient to meet BS1 criteria). The p.Ser102Asn variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Ser102Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ser102Asn variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 08, 2024This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 102 of the TCF4 protein (p.Ser102Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TCF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 207529). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxAug 05, 2022See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Benign
-0.48
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.021
.;.;T
Eigen
Benign
0.038
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.56
T;T;T
M_CAP
Benign
0.068
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-1.0
T
PROVEAN
Benign
-0.66
N;N;.
REVEL
Benign
0.14
Sift
Uncertain
0.0020
D;D;.
Sift4G
Uncertain
0.035
D;D;.
Vest4
0.39
MutPred
0.33
Gain of ubiquitination at K33 (P = 0.0339);Gain of ubiquitination at K33 (P = 0.0339);Gain of ubiquitination at K33 (P = 0.0339);
MVP
0.26
ClinPred
0.50
T
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.75
SpliceAI score (max)
0.040
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: rs796053413; hg19: chr18-53070749; API