rs7235757

Variant names:

• chr18-55400723-G-A
• rs7235757
• NM_001083962.2:c.369+2731C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-55400723-G-A
• chr18-55400723-G-C
• chr18-55400723-G-T

Variant summary

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

The NM_001083962.2(TCF4):​c.369+2731C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 206,642 control chromosomes in the GnomAD database, including 19,077 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 0.42 (15276 hom., cov: 31)
  • Exomes 𝑓: 0.36 (3801 hom.)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.743
• Publications: 13 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.369+2731C>T		intron_variant	Intron 6 of 19	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.369+2731C>T		intron_variant	Intron 6 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63837 AN: 151766 Hom.: 15224 Cov.: 31

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.415

GnomAD4 exome AF: 0.357 AC: 19566 AN: 54758 Hom.: 3801 AF XY: 0.357 AC XY: 10531 AN XY: 29494

African (AFR) AF: 0.682 AC: 1634 AN: 2396

American (AMR) AF: 0.375 AC: 1541 AN: 4108

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 472 AN: 1206

East Asian (EAS) AF: 0.517 AC: 2082 AN: 4028

South Asian (SAS) AF: 0.338 AC: 2627 AN: 7776

European-Finnish (FIN) AF: 0.248 AC: 354 AN: 1426

Middle Eastern (MID) AF: 0.423 AC: 83 AN: 196

European-Non Finnish (NFE) AF: 0.319 AC: 9884 AN: 31004

Other (OTH) AF: 0.340 AC: 889 AN: 2618

GnomAD4 genome AF: 0.421 AC: 63933 AN: 151884 Hom.: 15276 Cov.: 31 AF XY: 0.420 AC XY: 31183 AN XY: 74196

African (AFR) AF: 0.661 AC: 27391 AN: 41440

American (AMR) AF: 0.389 AC: 5938 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1193 AN: 3466

East Asian (EAS) AF: 0.487 AC: 2510 AN: 5152

South Asian (SAS) AF: 0.328 AC: 1579 AN: 4812

European-Finnish (FIN) AF: 0.280 AC: 2949 AN: 10518

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.309 AC: 20987 AN: 67944

Other (OTH) AF: 0.412 AC: 868 AN: 2106

Alfa AF: 0.339 Hom.: 15564

Bravo AF: 0.443

Asia WGS AF: 0.409 AC: 1425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.0
DANN	Benign	0.39
PhyloP100		0.74
PromoterAI		-0.011	Neutral
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: rs7235757; hg19: chr18-53067954;