chr18-55586153-G-GAGCAGC

Variant names:

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

Variant summary

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

The NM_001083962.2(TCF4):​c.73-807_73-802dupGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (108 hom., cov: 0)
  • Exomes 𝑓: 0.020 (1097 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

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

• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0739 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_73-802dupGCTGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-807_379-802dupGCTGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-807_73-802dupGCTGCT		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_73-802dupGCTGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-807_379-802dupGCTGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-807_73-802dupGCTGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2451 AN: 135386 Hom.: 108 Cov.: 0

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.0440

Gnomad SAS AF: 0.0326

Gnomad FIN AF: 0.00679

Gnomad MID AF: 0.0265

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0189

GnomAD4 exome AF: 0.0201 AC: 11481 AN: 571286 Hom.: 1097 Cov.: 0 AF XY: 0.0210 AC XY: 6280 AN XY: 298490

African (AFR) AF: 0.0107 AC: 193 AN: 17996

American (AMR) AF: 0.0109 AC: 240 AN: 21986

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 405 AN: 14882

East Asian (EAS) AF: 0.0768 AC: 1831 AN: 23834

South Asian (SAS) AF: 0.0294 AC: 1559 AN: 53038

European-Finnish (FIN) AF: 0.0179 AC: 417 AN: 23254

Middle Eastern (MID) AF: 0.0206 AC: 50 AN: 2422

European-Non Finnish (NFE) AF: 0.0159 AC: 6134 AN: 386164

Other (OTH) AF: 0.0235 AC: 652 AN: 27710

GnomAD4 genome AF: 0.0181 AC: 2453 AN: 135478 Hom.: 108 Cov.: 0 AF XY: 0.0179 AC XY: 1171 AN XY: 65526

African (AFR) AF: 0.0146 AC: 548 AN: 37642

American (AMR) AF: 0.0131 AC: 169 AN: 12936

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 90 AN: 3176

East Asian (EAS) AF: 0.0436 AC: 191 AN: 4380

South Asian (SAS) AF: 0.0334 AC: 133 AN: 3988

European-Finnish (FIN) AF: 0.00679 AC: 62 AN: 9126

Middle Eastern (MID) AF: 0.0286 AC: 8 AN: 280

European-Non Finnish (NFE) AF: 0.0195 AC: 1195 AN: 61234

Other (OTH) AF: 0.0181 AC: 34 AN: 1876

Alfa AF: 0.0156 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;