chr18-55400723-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001083962.2(TCF4):​c.369+2731C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083962.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	NM_001083962.2	MANE Select	c.369+2731C>G		intron	N/A	NP_001077431.1
	TCF4	NM_001243226.3		c.675+2731C>G		intron	N/A	NP_001230155.2
	TCF4	NM_001243228.2		c.369+2731C>G		intron	N/A	NP_001230157.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	ENST00000354452.8	TSL:5 MANE Select	c.369+2731C>G		intron	N/A	ENSP00000346440.3
	TCF4	ENST00000398339.5	TSL:1	c.675+2731C>G		intron	N/A	ENSP00000381382.1
	TCF4	ENST00000356073.8	TSL:1	c.369+2731C>G		intron	N/A	ENSP00000348374.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 54934 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 29600

African (AFR) AF: 0.00 AC: 0 AN: 2396

American (AMR) AF: 0.00 AC: 0 AN: 4112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1208

East Asian (EAS) AF: 0.00 AC: 0 AN: 4048

South Asian (SAS) AF: 0.00 AC: 0 AN: 7798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 31118

Other (OTH) AF: 0.00 AC: 0 AN: 2624

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 15564

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.8
DANN	Benign	0.26
PhyloP100		0.74
PromoterAI		-0.027	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;