NM_001083962.2:c.73-810_73-802dupGCTGCTGCT

Variant names:

• chr18-55586153-G-GAGCAGCAGC
• rs55725917
• NM_001083962.2:c.73-810_73-802dupGCTGCTGCT

Variant summary

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

The NM_001083962.2(TCF4):​c.73-810_73-802dupGCTGCTGCT 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 0.0096 (40 hom., cov: 0)
  • Exomes 𝑓: 0.012 (460 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.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0096 (1301/135494) while in subpopulation EAS AF = 0.0253 (111/4380). AF 95% confidence interval is 0.0215. There are 40 homozygotes in GnomAd4. There are 670 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1301 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.73-810_73-802dupGCTGCTGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-810_379-802dupGCTGCTGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-810_73-802dupGCTGCTGCT		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.73-810_73-802dupGCTGCTGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-810_379-802dupGCTGCTGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-810_73-802dupGCTGCTGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.00960 AC: 1300 AN: 135404 Hom.: 39 Cov.: 0

Gnomad AFR AF: 0.00650

Gnomad AMI AF: 0.0156

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00850

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.0206

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.0197

Gnomad NFE AF: 0.00877

Gnomad OTH AF: 0.00808

GnomAD4 exome AF: 0.0120 AC: 6837 AN: 571604 Hom.: 460 Cov.: 0 AF XY: 0.0125 AC XY: 3746 AN XY: 298616

African (AFR) AF: 0.00583 AC: 105 AN: 18020

American (AMR) AF: 0.00500 AC: 110 AN: 21988

Ashkenazi Jewish (ASJ) AF: 0.00989 AC: 147 AN: 14870

East Asian (EAS) AF: 0.0470 AC: 1122 AN: 23882

South Asian (SAS) AF: 0.0204 AC: 1083 AN: 53018

European-Finnish (FIN) AF: 0.0367 AC: 855 AN: 23308

Middle Eastern (MID) AF: 0.0193 AC: 47 AN: 2436

European-Non Finnish (NFE) AF: 0.00774 AC: 2990 AN: 386376

Other (OTH) AF: 0.0136 AC: 378 AN: 27706

GnomAD4 genome AF: 0.00960 AC: 1301 AN: 135494 Hom.: 40 Cov.: 0 AF XY: 0.0102 AC XY: 670 AN XY: 65518

African (AFR) AF: 0.00648 AC: 244 AN: 37654

American (AMR) AF: 0.00603 AC: 78 AN: 12944

Ashkenazi Jewish (ASJ) AF: 0.00850 AC: 27 AN: 3176

East Asian (EAS) AF: 0.0253 AC: 111 AN: 4380

South Asian (SAS) AF: 0.0211 AC: 84 AN: 3984

European-Finnish (FIN) AF: 0.0205 AC: 187 AN: 9112

Middle Eastern (MID) AF: 0.0213 AC: 6 AN: 282

European-Non Finnish (NFE) AF: 0.00875 AC: 536 AN: 61250

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		0.0
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;