18-55403518-C-T

Position:

• chr18-55403518-C-T

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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.305G>A	p.Ser102Asn	missense_variant, splice_region_variant	6/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.305G>A	p.Ser102Asn	missense_variant, splice_region_variant	6/20	5	NM_001083962.2	P3

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pitt-Hopkins syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

- -

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
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;N
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;