rs12455881

chr18-55585054-G-Achr18-55585054-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001083962.2(TCF4):c.145+226C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 151,964 control chromosomes in the GnomAD database, including 1,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1851 hom., cov: 32)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0760

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 18-55585054-G-A is Benign according to our data. Variant chr18-55585054-G-A is described in ClinVar as [Benign]. Clinvar id is 670700.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.145+226C>T		intron_variant		ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.145+226C>T		intron_variant		5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21001 AN: 151846 Hom.: 1845 Cov.: 32

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0918

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.140

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.138 AC: 21023 AN: 151964 Hom.: 1851 Cov.: 32 AF XY: 0.142 AC XY: 10513 AN XY: 74290

Gnomad4 AFR AF: 0.0460

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.0916

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.145

Alfa AF: 0.155 Hom.: 254

Bravo AF: 0.142

Asia WGS AF: 0.149 AC: 518 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	13
Dann	Benign	0.71

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

Other links and lift over

dbSNP: rs12455881; hg19: chr18-53252285;