18-55222481-GAA-GA

Variant names:

• chr18-55222481-GA-G
• rs71670792
• NM_001083962.2:c.*5553delT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001083962.2(TCF4):​c.*5553delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (24 hom., cov: 0)
  • Exomes 𝑓: 0.072 (0 hom.)
• Consequence: TCF4 NM_001083962.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00943 (1350/143120) while in subpopulation AFR AF = 0.0283 (1093/38642). AF 95% confidence interval is 0.0269. There are 24 homozygotes in GnomAd4. There are 690 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1350 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.*5553delT		3_prime_UTR	Exon 20 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.*5553delT		3_prime_UTR	Exon 21 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.*5553delT		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.*5553delT		3_prime_UTR	Exon 20 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000356073.8	TSL:1	c.*5553delT		3_prime_UTR	Exon 20 of 20	ENSP00000348374.4	P15884-1
	TCF4	ENST00000638154.3	TSL:5	c.*5553delT		3_prime_UTR	Exon 19 of 19	ENSP00000490625.2	A0A1B0GVR6

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1346 AN: 143092 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00640

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00525

Gnomad SAS AF: 0.0109

Gnomad FIN AF: 0.00138

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000962

Gnomad OTH AF: 0.00709

GnomAD4 exome AF: 0.0719 AC: 23 AN: 320 Hom.: 0 Cov.: 0 AF XY: 0.0865 AC XY: 18 AN XY: 208

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.0732 AC: 23 AN: 314

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00943 AC: 1350 AN: 143120 Hom.: 24 Cov.: 0 AF XY: 0.00996 AC XY: 690 AN XY: 69274

African (AFR) AF: 0.0283 AC: 1093 AN: 38642

American (AMR) AF: 0.00639 AC: 92 AN: 14392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3342

East Asian (EAS) AF: 0.00527 AC: 26 AN: 4938

South Asian (SAS) AF: 0.0110 AC: 49 AN: 4464

European-Finnish (FIN) AF: 0.00138 AC: 12 AN: 8726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000962 AC: 63 AN: 65460

Other (OTH) AF: 0.00754 AC: 15 AN: 1990

Alfa AF: 0.00 Hom.: 212

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pitt-Hopkins syndrome (1)

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; COSMIC: COSV61891055; COSMIC: COSV61891055;