18-55394706-G-C

Variant names:

• chr18-55394706-G-C
• rs3794889
• NM_001083962.2:c.369+8748C>G

Variant summary

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

The NM_001083962.2(TCF4):​c.369+8748C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,162 control chromosomes in the GnomAD database, including 5,098 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 0.25 (5098 hom., cov: 33)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.302

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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.369+8748C>G		intron_variant	Intron 6 of 19	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.369+8748C>G		intron_variant	Intron 6 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38406 AN: 152044 Hom.: 5095 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.280

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

GnomAD4 genome AF: 0.252 AC: 38413 AN: 152162 Hom.: 5098 Cov.: 33 AF XY: 0.255 AC XY: 18954 AN XY: 74382

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.278

Alfa AF: 0.134 Hom.: 213

Bravo AF: 0.261

Asia WGS AF: 0.292 AC: 1013 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.8
DANN	Benign	0.23

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: rs3794889; hg19: chr18-53061937;