rs1631486

Positions:

• chr18-55359126-G-A
• chr18-55359126-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001083962.2(TCF4):​c.370-8123C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 151,932 control chromosomes in the GnomAD database, including 20,428 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (20428 hom., cov: 32)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.370-8123C>T		intron_variant		ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.370-8123C>T		intron_variant		5	NM_001083962.2	ENSP00000346440	P3

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74203 AN: 151812 Hom.: 20377 Cov.: 32

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.468

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

GnomAD4 genome AF: 0.489 AC: 74296 AN: 151932 Hom.: 20428 Cov.: 32 AF XY: 0.488 AC XY: 36246 AN XY: 74236

Gnomad4 AFR AF: 0.763

Gnomad4 AMR AF: 0.432

Gnomad4 ASJ AF: 0.440

Gnomad4 EAS AF: 0.576

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.375

Gnomad4 NFE AF: 0.360

Gnomad4 OTH AF: 0.465

Alfa AF: 0.395 Hom.: 15401

Bravo AF: 0.513

Asia WGS AF: 0.469 AC: 1633 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.34
DANN	Benign	0.36

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: rs1631486; hg19: chr18-53026357;