rs9957668

chr18-55510439-T-C

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.146-46302A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 505,256 control chromosomes in the GnomAD database, including 30,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (8996 hom., cov: 32)
  • Exomes 𝑓: 0.35 (21685 hom.)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.88

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=-0.9).
• BP6: Variant 18-55510439-T-C is Benign according to our data. Variant chr18-55510439-T-C is described in ClinVar as [Benign]. Clinvar id is 679855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.146-46302A>G		intron_variant		ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.146-46302A>G		intron_variant		5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51606 AN: 151908 Hom.: 8995 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.345 AC: 122008 AN: 353230 Hom.: 21685 AF XY: 0.343 AC XY: 61043 AN XY: 178116

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.436

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.340 AC: 51613 AN: 152026 Hom.: 8996 Cov.: 32 AF XY: 0.337 AC XY: 25006 AN XY: 74296

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.498

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.359

Gnomad4 OTH AF: 0.327

Alfa AF: 0.356 Hom.: 16887

Bravo AF: 0.333

Asia WGS AF: 0.367 AC: 1281 AN: 3478

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 19, 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	-0.90
Cadd	Benign	0.39
Dann	Benign	0.48

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: rs9957668; hg19: chr18-53177670; COSMIC: COSV61902129;