rs9320010

Variant names:

• chr18-55386666-A-G
• rs9320010
• NM_001083962.2:c.369+16788T>C

Your query was ambiguous. Multiple possible variants found:

• chr18-55386666-A-G
• chr18-55386666-A-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+16788T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 152,040 control chromosomes in the GnomAD database, including 19,384 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 0.49 (19384 hom., cov: 32)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.918
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

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+16788T>C		intron	N/A	NP_001077431.1
	TCF4	NM_001243226.3		c.675+16788T>C		intron	N/A	NP_001230155.2
	TCF4	NM_001243228.2		c.369+16788T>C		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+16788T>C		intron	N/A	ENSP00000346440.3
	TCF4	ENST00000398339.5	TSL:1	c.675+16788T>C		intron	N/A	ENSP00000381382.1
	TCF4	ENST00000356073.8	TSL:1	c.369+16788T>C		intron	N/A	ENSP00000348374.4

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73983 AN: 151920 Hom.: 19349 Cov.: 32

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.479

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

GnomAD4 genome AF: 0.487 AC: 74059 AN: 152040 Hom.: 19384 Cov.: 32 AF XY: 0.486 AC XY: 36141 AN XY: 74334

African (AFR) AF: 0.707 AC: 29319 AN: 41452

American (AMR) AF: 0.435 AC: 6634 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3470

East Asian (EAS) AF: 0.491 AC: 2540 AN: 5174

South Asian (SAS) AF: 0.352 AC: 1699 AN: 4824

European-Finnish (FIN) AF: 0.379 AC: 4004 AN: 10578

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26755 AN: 67962

Other (OTH) AF: 0.476 AC: 1003 AN: 2108

Alfa AF: 0.444 Hom.: 3372

Bravo AF: 0.508

Asia WGS AF: 0.423 AC: 1474 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.28
DANN	Benign	0.45
PhyloP100		-0.92
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: rs9320010; hg19: chr18-53053897;