chr18-55586153-G-GAGCAGCAGCAGC

Variant names:

• chr18-55586153-G-GAGCAGCAGCAGC
• rs55725917
• NM_001083962.2:c.73-813_73-802dupGCTGCTGCTGCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001083962.2(TCF4):​c.73-813_73-802dupGCTGCTGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 0.0054 (14 hom., cov: 0)
  • Exomes 𝑓: 0.0072 (118 hom.)
  • Failed GnomAD Quality Control
• 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.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00538 (729/135528) while in subpopulation EAS AF = 0.0194 (85/4382). AF 95% confidence interval is 0.0161. There are 14 homozygotes in GnomAd4. There are 363 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 729 AD gene.

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.73-813_73-802dupGCTGCTGCTGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-813_379-802dupGCTGCTGCTGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-813_73-802dupGCTGCTGCTGCT		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.73-813_73-802dupGCTGCTGCTGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-813_379-802dupGCTGCTGCTGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-813_73-802dupGCTGCTGCTGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 730 AN: 135436 Hom.: 14 Cov.: 0

Gnomad AFR AF: 0.00429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00371

Gnomad ASJ AF: 0.0129

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00636

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.00449

Gnomad OTH AF: 0.00485

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00716 AC: 4096 AN: 571902 Hom.: 118 Cov.: 0 AF XY: 0.00771 AC XY: 2302 AN XY: 298748

African (AFR) AF: 0.00394 AC: 71 AN: 18018

American (AMR) AF: 0.00341 AC: 75 AN: 21988

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 222 AN: 14874

East Asian (EAS) AF: 0.0339 AC: 813 AN: 23968

South Asian (SAS) AF: 0.0145 AC: 769 AN: 53116

European-Finnish (FIN) AF: 0.0145 AC: 339 AN: 23334

Middle Eastern (MID) AF: 0.0107 AC: 26 AN: 2432

European-Non Finnish (NFE) AF: 0.00402 AC: 1552 AN: 386450

Other (OTH) AF: 0.00826 AC: 229 AN: 27722

GnomAD4 genome AF: 0.00538 AC: 729 AN: 135528 Hom.: 14 Cov.: 0 AF XY: 0.00554 AC XY: 363 AN XY: 65542

African (AFR) AF: 0.00428 AC: 161 AN: 37660

American (AMR) AF: 0.00371 AC: 48 AN: 12938

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 41 AN: 3176

East Asian (EAS) AF: 0.0194 AC: 85 AN: 4382

South Asian (SAS) AF: 0.0128 AC: 51 AN: 3988

European-Finnish (FIN) AF: 0.00636 AC: 58 AN: 9124

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.00449 AC: 275 AN: 61266

Other (OTH) AF: 0.00480 AC: 9 AN: 1876

Alfa AF: 0.00 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;