NM_001083962.2:c.73-807_73-802delGCTGCT

Variant names:

• chr18-55586153-GAGCAGC-G
• rs55725917
• NM_001083962.2:c.73-807_73-802delGCTGCT

Variant summary

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

The NM_001083962.2(TCF4):​c.73-807_73-802delGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 570,520 control chromosomes in the GnomAD database, including 244 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (73 hom., cov: 0)
  • Exomes 𝑓: 0.015 (244 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.819
• 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

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

• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0535 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.73-807_73-802delGCTGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-807_379-802delGCTGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-807_73-802delGCTGCT		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.73-807_73-802delGCTGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-807_379-802delGCTGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-807_73-802delGCTGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3116 AN: 135326 Hom.: 73 Cov.: 0

Gnomad AFR AF: 0.0515

Gnomad AMI AF: 0.00239

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.0357

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00955

Gnomad OTH AF: 0.0221

GnomAD4 exome AF: 0.0148 AC: 8421 AN: 570520 Hom.: 244 AF XY: 0.0158 AC XY: 4717 AN XY: 298040

African (AFR) AF: 0.0372 AC: 668 AN: 17942

American (AMR) AF: 0.00929 AC: 204 AN: 21960

Ashkenazi Jewish (ASJ) AF: 0.0296 AC: 439 AN: 14850

East Asian (EAS) AF: 0.0560 AC: 1323 AN: 23606

South Asian (SAS) AF: 0.0350 AC: 1854 AN: 52910

European-Finnish (FIN) AF: 0.00974 AC: 227 AN: 23314

Middle Eastern (MID) AF: 0.0185 AC: 45 AN: 2432

European-Non Finnish (NFE) AF: 0.00815 AC: 3146 AN: 385864

Other (OTH) AF: 0.0186 AC: 515 AN: 27642

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0230 AC: 3118 AN: 135418 Hom.: 73 Cov.: 0 AF XY: 0.0226 AC XY: 1481 AN XY: 65484

African (AFR) AF: 0.0515 AC: 1937 AN: 37592

American (AMR) AF: 0.0121 AC: 157 AN: 12936

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 97 AN: 3176

East Asian (EAS) AF: 0.0272 AC: 119 AN: 4376

South Asian (SAS) AF: 0.0349 AC: 139 AN: 3978

European-Finnish (FIN) AF: 0.00405 AC: 37 AN: 9126

Middle Eastern (MID) AF: 0.0177 AC: 5 AN: 282

European-Non Finnish (NFE) AF: 0.00955 AC: 585 AN: 61240

Other (OTH) AF: 0.0213 AC: 40 AN: 1874

Alfa AF: 0.00 Hom.: 287

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.82
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;