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

Variant names:

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

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_73-802delGCTGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 706,820 control chromosomes in the GnomAD database, including 173 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 0.018 (47 hom., cov: 0)
  • Exomes 𝑓: 0.0074 (126 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 = 0.0182 (2465/135436) while in subpopulation AFR AF = 0.0473 (1780/37602). AF 95% confidence interval is 0.0455. There are 47 homozygotes in GnomAd4. There are 1237 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2465 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_73-802delGCTGCTGCT		intron	N/A	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.379-810_379-802delGCTGCTGCT		intron	N/A	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.73-810_73-802delGCTGCTGCT		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_73-802delGCTGCTGCT		intron	N/A	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.379-810_379-802delGCTGCTGCT		intron	N/A	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.73-810_73-802delGCTGCTGCT		intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2458 AN: 135344 Hom.: 46 Cov.: 0

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00866

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.00164

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.0205

GnomAD4 exome AF: 0.00740 AC: 4228 AN: 571384 Hom.: 126 AF XY: 0.00759 AC XY: 2265 AN XY: 298536

African (AFR) AF: 0.0353 AC: 633 AN: 17936

American (AMR) AF: 0.00678 AC: 149 AN: 21972

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 208 AN: 14836

East Asian (EAS) AF: 0.0140 AC: 333 AN: 23822

South Asian (SAS) AF: 0.0128 AC: 678 AN: 53066

European-Finnish (FIN) AF: 0.00317 AC: 74 AN: 23342

Middle Eastern (MID) AF: 0.00988 AC: 24 AN: 2430

European-Non Finnish (NFE) AF: 0.00466 AC: 1801 AN: 386294

Other (OTH) AF: 0.0118 AC: 328 AN: 27686

GnomAD4 genome AF: 0.0182 AC: 2465 AN: 135436 Hom.: 47 Cov.: 0 AF XY: 0.0189 AC XY: 1237 AN XY: 65494

African (AFR) AF: 0.0473 AC: 1780 AN: 37602

American (AMR) AF: 0.0107 AC: 139 AN: 12934

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 35 AN: 3174

East Asian (EAS) AF: 0.00868 AC: 38 AN: 4376

South Asian (SAS) AF: 0.0136 AC: 54 AN: 3980

European-Finnish (FIN) AF: 0.00164 AC: 15 AN: 9126

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

European-Non Finnish (NFE) AF: 0.00589 AC: 361 AN: 61250

Other (OTH) AF: 0.0203 AC: 38 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		0.89
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;