chr18-55586153-GAGCAGCAGC-G

Variant names:

• chr18-55586153-GAGCAGCAGC-G
• rs55725917
• NM_001083962.2:c.73-810_73-802delGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001083962.2(TCF4):​c.73-810_73-802delGCTGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 706,820 control chromosomes in the GnomAD database, including 173 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (47 hom., cov: 0)
  • Exomes 𝑓: 0.0074 (126 hom.)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.885

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.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0182 (2465/135436) while in subpopulation AFR AF= 0.0473 (1780/37602). AF 95% confidence interval is 0.0455. There are 47 homozygotes in gnomad4. There are 1237 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2465 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.73-810_73-802delGCTGCTGCT		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.73-810_73-802delGCTGCTGCT		intron_variant	Intron 2 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2458 AN: 135344 Hom.: 46 Cov.: 0

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00866

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.00164

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.0205

GnomAD4 exome AF: 0.00740 AC: 4228 AN: 571384 Hom.: 126 AF XY: 0.00759 AC XY: 2265 AN XY: 298536

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.00678

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.0140

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.00317

Gnomad4 NFE exome AF: 0.00466

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.0182 AC: 2465 AN: 135436 Hom.: 47 Cov.: 0 AF XY: 0.0189 AC XY: 1237 AN XY: 65494

Gnomad4 AFR AF: 0.0473

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00868

Gnomad4 SAS AF: 0.0136

Gnomad4 FIN AF: 0.00164

Gnomad4 NFE AF: 0.00589

Gnomad4 OTH AF: 0.0203

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;