rs2919451

Variant names:

• chr18-55417069-C-T
• rs2919451
• NM_001083962.2:c.305-13551G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001083962.2(TCF4):​c.305-13551G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,126 control chromosomes in the GnomAD database, including 21,178 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 0.50 (21178 hom., cov: 33)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.774
• Publications: 8 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.305-13551G>A		intron_variant	Intron 5 of 19	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.305-13551G>A		intron_variant	Intron 5 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.500 AC: 76056 AN: 152006 Hom.: 21124 Cov.: 33

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.486

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

GnomAD4 genome AF: 0.501 AC: 76154 AN: 152126 Hom.: 21178 Cov.: 33 AF XY: 0.499 AC XY: 37094 AN XY: 74368

African (AFR) AF: 0.770 AC: 31967 AN: 41502

American (AMR) AF: 0.443 AC: 6776 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1434 AN: 3468

East Asian (EAS) AF: 0.487 AC: 2518 AN: 5170

South Asian (SAS) AF: 0.349 AC: 1685 AN: 4824

European-Finnish (FIN) AF: 0.371 AC: 3923 AN: 10578

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.386 AC: 26219 AN: 67986

Other (OTH) AF: 0.482 AC: 1019 AN: 2112

Alfa AF: 0.456 Hom.: 3722

Bravo AF: 0.524

Asia WGS AF: 0.422 AC: 1469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2919451; hg19: chr18-53084300;