rs796053413

Variant names:

• chr18-55403518-C-T
• rs796053413
• NM_001083962.2:c.305G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

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 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCF4 NM_001083962.2 missense, splice_region
• Scores: Splicing: ADA: 0.9978
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 5.56

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]

ACMG classification

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
TCF4	NM_001083962.2	c.305G>A	p.Ser102Asn	missense_variant, splice_region_variant	Exon 6 of 20	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.305G>A	p.Ser102Asn	missense_variant, splice_region_variant	Exon 6 of 20	5	NM_001083962.2	ENSP00000346440.3

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

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:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Pitt-Hopkins syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2024	This 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. -
Likely benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jun 25, 2024	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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2022

See 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

Other links and lift over

dbSNP: rs796053413; hg19: chr18-53070749;