18-55586153-GAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC-GAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC

Variant names:

• chr18-55586153-G-GAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC
• rs55725917
• NM_001083962.2:c.73-843_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant summary

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

The NM_001083962.2(TCF4):​c.73-843_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00096 (55 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

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 sas. gnomad4 allele frequency = 0.000428 (58/135538) while in subpopulation SAS AF= 0.001 (4/3988). AF 95% confidence interval is 0.000352. There are 2 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.73-843_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT		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.73-843_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT		intron_variant	Intron 2 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.000428 AC: 58 AN: 135446 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000464

Gnomad ASJ AF: 0.000945

Gnomad EAS AF: 0.000683

Gnomad SAS AF: 0.00100

Gnomad FIN AF: 0.000329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000490

Gnomad OTH AF: 0.000539

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000964 AC: 552 AN: 572458 Hom.: 55 Cov.: 0 AF XY: 0.000996 AC XY: 298 AN XY: 299078

Gnomad4 AFR exome AF: 0.000555

Gnomad4 AMR exome AF: 0.000409

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00166

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.000910

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000428 AC: 58 AN: 135538 Hom.: 2 Cov.: 0 AF XY: 0.000534 AC XY: 35 AN XY: 65548

Gnomad4 AFR AF: 0.000212

Gnomad4 AMR AF: 0.000464

Gnomad4 ASJ AF: 0.000945

Gnomad4 EAS AF: 0.000685

Gnomad4 SAS AF: 0.00100

Gnomad4 FIN AF: 0.000329

Gnomad4 NFE AF: 0.000490

Gnomad4 OTH AF: 0.000533

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;