NM_001083962.2:c.73-819_73-802delGCTGCTGCTGCTGCTGCT

Variant names:

• chr18-55586153-GAGCAGCAGCAGCAGCAGC-G
• rs55725917
• NM_001083962.2:c.73-819_73-802delGCTGCTGCTGCTGCTGCT

Variant summary

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

The NM_001083962.2(TCF4):​c.73-819_73-802delGCTGCTGCTGCTGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00485 in 707,856 control chromosomes in the GnomAD database, including 113 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.010 (20 hom., cov: 0)
  • Exomes 𝑓: 0.0036 (93 hom.)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.885
• 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 afr. GnomAd4 allele frequency = 0.0102 (1387/135498) while in subpopulation AFR AF = 0.0265 (996/37628). AF 95% confidence interval is 0.0251. There are 20 homozygotes in GnomAd4. There are 671 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1387 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.73-819_73-802delGCTGCTGCTGCTGCTGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-819_379-802delGCTGCTGCTGCTGCTGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-819_73-802delGCTGCTGCTGCTGCTGCT		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.73-819_73-802delGCTGCTGCTGCTGCTGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-819_379-802delGCTGCTGCTGCTGCTGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-819_73-802delGCTGCTGCTGCTGCTGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1380 AN: 135406 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00580

Gnomad ASJ AF: 0.00126

Gnomad EAS AF: 0.00228

Gnomad SAS AF: 0.00727

Gnomad FIN AF: 0.00657

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.0102

GnomAD4 exome AF: 0.00358 AC: 2047 AN: 572358 Hom.: 93 AF XY: 0.00368 AC XY: 1100 AN XY: 299028

African (AFR) AF: 0.0199 AC: 358 AN: 17970

American (AMR) AF: 0.00427 AC: 94 AN: 22000

Ashkenazi Jewish (ASJ) AF: 0.000805 AC: 12 AN: 14908

East Asian (EAS) AF: 0.00195 AC: 47 AN: 24060

South Asian (SAS) AF: 0.00727 AC: 387 AN: 53200

European-Finnish (FIN) AF: 0.00741 AC: 173 AN: 23358

Middle Eastern (MID) AF: 0.00698 AC: 17 AN: 2436

European-Non Finnish (NFE) AF: 0.00212 AC: 820 AN: 386680

Other (OTH) AF: 0.00501 AC: 139 AN: 27746

GnomAD4 genome AF: 0.0102 AC: 1387 AN: 135498 Hom.: 20 Cov.: 0 AF XY: 0.0102 AC XY: 671 AN XY: 65536

African (AFR) AF: 0.0265 AC: 996 AN: 37628

American (AMR) AF: 0.00580 AC: 75 AN: 12940

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 4 AN: 3176

East Asian (EAS) AF: 0.00228 AC: 10 AN: 4382

South Asian (SAS) AF: 0.00727 AC: 29 AN: 3988

European-Finnish (FIN) AF: 0.00657 AC: 60 AN: 9126

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

European-Non Finnish (NFE) AF: 0.00315 AC: 193 AN: 61262

Other (OTH) AF: 0.0101 AC: 19 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		0.89
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;