rs17597926

chr18-55538707-G-Achr18-55538707-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001083962.2(TCF4):c.145+46573C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 152,158 control chromosomes in the GnomAD database, including 68 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 (68 hom., cov: 32)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.446

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3256/152158) while in subpopulation NFE AF= 0.0258 (1756/68004). AF 95% confidence interval is 0.0248. There are 68 homozygotes in gnomad4. There are 1619 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3258 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.145+46573C>T		intron_variant		ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.145+46573C>T		intron_variant		5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3258 AN: 152038 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.0655

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00416

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0269

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

GnomAD4 genome AF: 0.0214 AC: 3256 AN: 152158 Hom.: 68 Cov.: 32 AF XY: 0.0218 AC XY: 1619 AN XY: 74374

Gnomad4 AFR AF: 0.00515

Gnomad4 AMR AF: 0.0251

Gnomad4 ASJ AF: 0.0655

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00416

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0258

Gnomad4 OTH AF: 0.0266

Alfa AF: 0.0223 Hom.: 1

Bravo AF: 0.0207

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	0.44
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17597926; hg19: chr18-53205938;