chr18-55586153-G-GAGC

Variant names:

• chr18-55586153-G-GAGC
• rs55725917
• NM_001083962.2:c.73-804_73-802dupGCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001083962.2(TCF4):​c.73-804_73-802dupGCT 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. The gene TCF4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.023 (154 hom., cov: 0)
  • Exomes 𝑓: 0.026 (1709 hom.)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 0 publications found

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]

TCF4 Gene-Disease associations (from GenCC):

• Pitt-Hopkins syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• corneal dystrophy, Fuchs endothelial, 3

  Inheritance: AD Classification: STRONG Submitted by: G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Specifications for TCF4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083962.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	NM_001083962.2	MANE Select	c.73-804_73-802dupGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-804_379-802dupGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-804_73-802dupGCT		intron	N/A	NP_001230157.1	H3BTP3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	ENST00000354452.8	TSL:5 MANE Select	c.73-804_73-802dupGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-804_379-802dupGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-804_73-802dupGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3150 AN: 135290 Hom.: 154 Cov.: 0

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00358

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0719

Gnomad EAS AF: 0.0479

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.00756

Gnomad MID AF: 0.00993

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0194

GnomAD4 exome AF: 0.0259 AC: 14767 AN: 570250 Hom.: 1709 Cov.: 0 AF XY: 0.0270 AC XY: 8047 AN XY: 297900

African (AFR) AF: 0.0140 AC: 252 AN: 17994

American (AMR) AF: 0.0171 AC: 376 AN: 21950

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 1016 AN: 14826

East Asian (EAS) AF: 0.0627 AC: 1482 AN: 23634

South Asian (SAS) AF: 0.0361 AC: 1907 AN: 52894

European-Finnish (FIN) AF: 0.0163 AC: 380 AN: 23322

Middle Eastern (MID) AF: 0.0343 AC: 83 AN: 2420

European-Non Finnish (NFE) AF: 0.0217 AC: 8363 AN: 385588

Other (OTH) AF: 0.0329 AC: 908 AN: 27622

GnomAD4 genome AF: 0.0233 AC: 3152 AN: 135382 Hom.: 154 Cov.: 0 AF XY: 0.0225 AC XY: 1471 AN XY: 65474

African (AFR) AF: 0.0163 AC: 613 AN: 37642

American (AMR) AF: 0.0170 AC: 219 AN: 12920

Ashkenazi Jewish (ASJ) AF: 0.0719 AC: 228 AN: 3170

East Asian (EAS) AF: 0.0478 AC: 209 AN: 4374

South Asian (SAS) AF: 0.0322 AC: 128 AN: 3974

European-Finnish (FIN) AF: 0.00756 AC: 69 AN: 9124

Middle Eastern (MID) AF: 0.0107 AC: 3 AN: 280

European-Non Finnish (NFE) AF: 0.0269 AC: 1644 AN: 61184

Other (OTH) AF: 0.0192 AC: 36 AN: 1876

Alfa AF: 0.0321 Hom.: 287

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs55725917; hg19: chr18-53253384;