18-55630760-T-C

Variant names:

• chr18-55630760-T-C
• rs17527346
• ENST00000398339.5:c.286+538A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001243226.3(TCF4):​c.286+538A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 152,268 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.021 (69 hom., cov: 32)
• Consequence: TCF4 NM_001243226.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, ClinGen
• 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

ENSG00000267284 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3232/152268) while in subpopulation NFE AF = 0.0258 (1755/68012). AF 95% confidence interval is 0.0248. There are 69 homozygotes in GnomAd4. There are 1606 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3232 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243226.3. 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_001243226.3		c.286+538A>G		intron	N/A	NP_001230155.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	ENST00000398339.5	TSL:1	c.286+538A>G		intron	N/A	ENSP00000381382.1
	TCF4	ENST00000565393.2	TSL:1	n.64+538A>G		intron	N/A	ENSP00000454441.2
	TCF4	ENST00000628391.1	TSL:1	n.19+4943A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3236 AN: 152150 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00488

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0263

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0212 AC: 3232 AN: 152268 Hom.: 69 Cov.: 32 AF XY: 0.0216 AC XY: 1606 AN XY: 74456

African (AFR) AF: 0.00484 AC: 201 AN: 41550

American (AMR) AF: 0.0246 AC: 376 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4824

European-Finnish (FIN) AF: 0.0387 AC: 411 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0258 AC: 1755 AN: 68012

Other (OTH) AF: 0.0261 AC: 55 AN: 2110

Alfa AF: 0.0308 Hom.: 24

Bravo AF: 0.0205

Asia WGS AF: 0.00231 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-0.37
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: rs17527346; hg19: chr18-53297991;