rs9960767

Variant names:

• chr18-55487771-A-C
• rs9960767
• NM_001083962.2:c.146-23634T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-55487771-A-C
• chr18-55487771-A-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001083962.2(TCF4):​c.146-23634T>G variant causes a intron change. The variant allele was found at a frequency of 0.108 in 152,092 control chromosomes in the GnomAD database, including 1,321 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 0.11 (1321 hom., cov: 32)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.07
• Publications: 90 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.146-23634T>G		intron_variant	Intron 3 of 19	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.146-23634T>G		intron_variant	Intron 3 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16454 AN: 151974 Hom.: 1309 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.0682

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.108 AC: 16493 AN: 152092 Hom.: 1321 Cov.: 32 AF XY: 0.111 AC XY: 8244 AN XY: 74360

African (AFR) AF: 0.215 AC: 8912 AN: 41450

American (AMR) AF: 0.0681 AC: 1041 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 331 AN: 3460

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5186

South Asian (SAS) AF: 0.229 AC: 1100 AN: 4814

European-Finnish (FIN) AF: 0.0713 AC: 755 AN: 10590

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0567 AC: 3855 AN: 67990

Other (OTH) AF: 0.102 AC: 215 AN: 2114

Alfa AF: 0.0724 Hom.: 1281

Bravo AF: 0.108

Asia WGS AF: 0.104 AC: 360 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		5.1
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: rs9960767; hg19: chr18-53155002;