NM_001083962.2:c.73-816_73-802delGCTGCTGCTGCTGCT

Variant names:

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

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_73-802delGCTGCTGCTGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00437 in 707,772 control chromosomes in the GnomAD database, including 100 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 0.013 (43 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (57 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 = 0.0126 (1702/135496) while in subpopulation AFR AF = 0.0392 (1475/37622). AF 95% confidence interval is 0.0375. There are 43 homozygotes in GnomAd4. There are 799 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1702 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_73-802delGCTGCTGCTGCTGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-816_379-802delGCTGCTGCTGCTGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-816_73-802delGCTGCTGCTGCTGCT		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_73-802delGCTGCTGCTGCTGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-816_379-802delGCTGCTGCTGCTGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-816_73-802delGCTGCTGCTGCTGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1697 AN: 135404 Hom.: 42 Cov.: 0

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00315

Gnomad EAS AF: 0.00273

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.000329

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00862

GnomAD4 exome AF: 0.00243 AC: 1392 AN: 572276 Hom.: 57 AF XY: 0.00241 AC XY: 722 AN XY: 298988

African (AFR) AF: 0.0270 AC: 484 AN: 17948

American (AMR) AF: 0.00250 AC: 55 AN: 21996

Ashkenazi Jewish (ASJ) AF: 0.00275 AC: 41 AN: 14906

East Asian (EAS) AF: 0.00462 AC: 111 AN: 24024

South Asian (SAS) AF: 0.00314 AC: 167 AN: 53220

European-Finnish (FIN) AF: 0.00103 AC: 24 AN: 23362

Middle Eastern (MID) AF: 0.00453 AC: 11 AN: 2430

European-Non Finnish (NFE) AF: 0.000936 AC: 362 AN: 386652

Other (OTH) AF: 0.00494 AC: 137 AN: 27738

GnomAD4 genome AF: 0.0126 AC: 1702 AN: 135496 Hom.: 43 Cov.: 0 AF XY: 0.0122 AC XY: 799 AN XY: 65528

African (AFR) AF: 0.0392 AC: 1475 AN: 37622

American (AMR) AF: 0.00641 AC: 83 AN: 12940

Ashkenazi Jewish (ASJ) AF: 0.00315 AC: 10 AN: 3176

East Asian (EAS) AF: 0.00274 AC: 12 AN: 4382

South Asian (SAS) AF: 0.00627 AC: 25 AN: 3988

European-Finnish (FIN) AF: 0.000329 AC: 3 AN: 9126

Middle Eastern (MID) AF: 0.0142 AC: 4 AN: 282

European-Non Finnish (NFE) AF: 0.00122 AC: 75 AN: 61266

Other (OTH) AF: 0.00800 AC: 15 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;