18-55586153-GAGC-G

Variant names:

• chr18-55586153-GAGC-G
• rs55725917
• NM_001083962.2:c.73-804_73-802delGCT

Variant summary

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

The NM_001083962.2(TCF4):​c.73-804_73-802delGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 702,900 control chromosomes in the GnomAD database, including 277 homozygotes. 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 0.023 (24 hom., cov: 0)
  • Exomes 𝑓: 0.022 (253 hom.)
• 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.

• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0788 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.73-804_73-802delGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-804_379-802delGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-804_73-802delGCT		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.73-804_73-802delGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-804_379-802delGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-804_73-802delGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3075 AN: 135234 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.0167

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0319

Gnomad EAS AF: 0.0459

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0362

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0270

GnomAD4 exome AF: 0.0220 AC: 12464 AN: 567574 Hom.: 253 AF XY: 0.0235 AC XY: 6972 AN XY: 296492

African (AFR) AF: 0.0253 AC: 453 AN: 17914

American (AMR) AF: 0.0151 AC: 330 AN: 21862

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 460 AN: 14780

East Asian (EAS) AF: 0.0818 AC: 1921 AN: 23484

South Asian (SAS) AF: 0.0419 AC: 2208 AN: 52682

European-Finnish (FIN) AF: 0.0150 AC: 346 AN: 23094

Middle Eastern (MID) AF: 0.0310 AC: 75 AN: 2418

European-Non Finnish (NFE) AF: 0.0154 AC: 5913 AN: 383880

Other (OTH) AF: 0.0276 AC: 758 AN: 27460

GnomAD4 genome AF: 0.0227 AC: 3078 AN: 135326 Hom.: 24 Cov.: 0 AF XY: 0.0227 AC XY: 1485 AN XY: 65444

African (AFR) AF: 0.0294 AC: 1106 AN: 37574

American (AMR) AF: 0.0166 AC: 214 AN: 12926

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 101 AN: 3170

East Asian (EAS) AF: 0.0460 AC: 201 AN: 4372

South Asian (SAS) AF: 0.0405 AC: 161 AN: 3972

European-Finnish (FIN) AF: 0.0104 AC: 95 AN: 9126

Middle Eastern (MID) AF: 0.0390 AC: 11 AN: 282

European-Non Finnish (NFE) AF: 0.0184 AC: 1124 AN: 61194

Other (OTH) AF: 0.0272 AC: 51 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		0.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55725917; hg19: chr18-53253384;