18-55586153-G-GAGCAGCAGCAGCAGC

Variant names:

• chr18-55586153-G-GAGCAGCAGCAGCAGC
• rs55725917
• NM_001083962.2:c.73-816_73-802dupGCTGCTGCTGCTGCT

Variant summary

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

The NM_001083962.2(TCF4):​c.73-816_73-802dupGCTGCTGCTGCTGCT 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 0.0051 (14 hom., cov: 0)
  • Exomes 𝑓: 0.0061 (91 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 = 0.00512 (694/135506) while in subpopulation EAS AF = 0.0116 (51/4380). AF 95% confidence interval is 0.0091. There are 14 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 694 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.73-816_73-802dupGCTGCTGCTGCTGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-816_379-802dupGCTGCTGCTGCTGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-816_73-802dupGCTGCTGCTGCTGCT		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.73-816_73-802dupGCTGCTGCTGCTGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-816_379-802dupGCTGCTGCTGCTGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-816_73-802dupGCTGCTGCTGCTGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 693 AN: 135414 Hom.: 14 Cov.: 0

Gnomad AFR AF: 0.00455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00431

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00607 AC: 3473 AN: 571812 Hom.: 91 Cov.: 0 AF XY: 0.00628 AC XY: 1877 AN XY: 298730

African (AFR) AF: 0.00372 AC: 67 AN: 18016

American (AMR) AF: 0.00382 AC: 84 AN: 21978

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 267 AN: 14878

East Asian (EAS) AF: 0.0174 AC: 417 AN: 24018

South Asian (SAS) AF: 0.00849 AC: 451 AN: 53140

European-Finnish (FIN) AF: 0.00797 AC: 186 AN: 23328

Middle Eastern (MID) AF: 0.00822 AC: 20 AN: 2432

European-Non Finnish (NFE) AF: 0.00462 AC: 1785 AN: 386302

Other (OTH) AF: 0.00707 AC: 196 AN: 27720

GnomAD4 genome AF: 0.00512 AC: 694 AN: 135506 Hom.: 14 Cov.: 0 AF XY: 0.00511 AC XY: 335 AN XY: 65534

African (AFR) AF: 0.00459 AC: 173 AN: 37656

American (AMR) AF: 0.00425 AC: 55 AN: 12940

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 64 AN: 3174

East Asian (EAS) AF: 0.0116 AC: 51 AN: 4380

South Asian (SAS) AF: 0.00928 AC: 37 AN: 3988

European-Finnish (FIN) AF: 0.00537 AC: 49 AN: 9118

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.00415 AC: 254 AN: 61254

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;