18-55586153-GAGCAGC-G

Variant names:

• chr18-55586153-GAGCAGC-G
• rs55725917
• NM_001083962.2:c.73-807_73-802delGCTGCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001083962.2(TCF4):​c.73-807_73-802delGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 570,520 control chromosomes in the GnomAD database, including 244 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (73 hom., cov: 0)
  • Exomes 𝑓: 0.015 (244 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.819

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 -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.73-807_73-802delGCTGCT		intron_variant	Intron 2 of 19	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.73-807_73-802delGCTGCT		intron_variant	Intron 2 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3116 AN: 135326 Hom.: 73 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0515

Gnomad AMI AF: 0.00239

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.0357

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00955

Gnomad OTH AF: 0.0221

GnomAD4 exome AF: 0.0148 AC: 8421 AN: 570520 Hom.: 244 AF XY: 0.0158 AC XY: 4717 AN XY: 298040

Gnomad4 AFR exome AF: 0.0372

Gnomad4 AMR exome AF: 0.00929

Gnomad4 ASJ exome AF: 0.0296

Gnomad4 EAS exome AF: 0.0560

Gnomad4 SAS exome AF: 0.0350

Gnomad4 FIN exome AF: 0.00974

Gnomad4 NFE exome AF: 0.00815

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0230 AC: 3118 AN: 135418 Hom.: 73 Cov.: 0 AF XY: 0.0226 AC XY: 1481 AN XY: 65484

Gnomad4 AFR AF: 0.0515

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.0272

Gnomad4 SAS AF: 0.0349

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00955

Gnomad4 OTH AF: 0.0213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55725917; hg19: chr18-53253384;