18-55222481-GAA-GAAAA

Variant names:

• chr18-55222481-G-GAA
• rs71670792
• NM_001083962.2:c.*5552_*5553dupTT

Variant summary

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

The NM_001083962.2(TCF4):​c.*5552_*5553dupTT variant causes a 3 prime UTR 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 0.0043 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF4 NM_001083962.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.662
• 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: Orphanet, ClinGen, G2P, Ambry Genetics, 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 nfe. GnomAd4 allele frequency = 0.00427 (611/143208) while in subpopulation NFE AF = 0.00638 (418/65502). AF 95% confidence interval is 0.00588. There are 2 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 611 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.*5552_*5553dupTT		3_prime_UTR	Exon 20 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.*5552_*5553dupTT		3_prime_UTR	Exon 21 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.*5552_*5553dupTT		3_prime_UTR	Exon 20 of 20	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.*5552_*5553dupTT		3_prime_UTR	Exon 20 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000356073.8	TSL:1	c.*5552_*5553dupTT		3_prime_UTR	Exon 20 of 20	ENSP00000348374.4	P15884-1
	TCF4	ENST00000638154.3	TSL:5	c.*5552_*5553dupTT		3_prime_UTR	Exon 19 of 19	ENSP00000490625.2	A0A1B0GVR6

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 610 AN: 143174 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00194

Gnomad AMI AF: 0.00450

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000807

Gnomad SAS AF: 0.00490

Gnomad FIN AF: 0.00229

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00761

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 344 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 218

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 338

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.00427 AC: 611 AN: 143208 Hom.: 2 Cov.: 0 AF XY: 0.00368 AC XY: 255 AN XY: 69324

African (AFR) AF: 0.00197 AC: 76 AN: 38648

American (AMR) AF: 0.00354 AC: 51 AN: 14408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3348

East Asian (EAS) AF: 0.000810 AC: 4 AN: 4940

South Asian (SAS) AF: 0.00492 AC: 22 AN: 4468

European-Finnish (FIN) AF: 0.00229 AC: 20 AN: 8740

Middle Eastern (MID) AF: 0.00360 AC: 1 AN: 278

European-Non Finnish (NFE) AF: 0.00638 AC: 418 AN: 65502

Other (OTH) AF: 0.00755 AC: 15 AN: 1988

Alfa AF: 0.000721 Hom.: 212

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
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: rs71670792; hg19: chr18-52889712;