18-55228300-T-C

Variant names:

• chr18-55228300-T-C
• rs8766
• NM_001083962.2:c.1941A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001083962.2(TCF4):​c.1941A>G​(p.Ser647Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,613,772 control chromosomes in the GnomAD database, including 115,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10510 hom., cov: 31)
  • Exomes 𝑓: 0.38 (105288 hom.)
• Consequence: TCF4 NM_001083962.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.06
• Publications: 35 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 18-55228300-T-C is Benign according to our data. Variant chr18-55228300-T-C is described in ClinVar as Benign. ClinVar VariationId is 93544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 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.1941A>G	p.Ser647Ser	synonymous	Exon 19 of 20	NP_001077431.1
	TCF4	NM_001243226.3		c.2247A>G	p.Ser749Ser	synonymous	Exon 20 of 21	NP_001230155.2
	TCF4	NM_001243228.2		c.1959A>G	p.Ser653Ser	synonymous	Exon 19 of 20	NP_001230157.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	ENST00000354452.8	TSL:5 MANE Select	c.1941A>G	p.Ser647Ser	synonymous	Exon 19 of 20	ENSP00000346440.3
	TCF4	ENST00000398339.5	TSL:1	c.2247A>G	p.Ser749Ser	synonymous	Exon 20 of 21	ENSP00000381382.1
	TCF4	ENST00000356073.8	TSL:1	c.1929A>G	p.Ser643Ser	synonymous	Exon 19 of 20	ENSP00000348374.4

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56295 AN: 151890 Hom.: 10500 Cov.: 31

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.375 AC: 94350 AN: 251378 AF XY: 0.372

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.444

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.378 AC: 552619 AN: 1461764 Hom.: 105288 Cov.: 43 AF XY: 0.376 AC XY: 273634 AN XY: 727182

African (AFR) AF: 0.319 AC: 10685 AN: 33480

American (AMR) AF: 0.365 AC: 16336 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 11672 AN: 26136

East Asian (EAS) AF: 0.405 AC: 16064 AN: 39696

South Asian (SAS) AF: 0.272 AC: 23463 AN: 86256

European-Finnish (FIN) AF: 0.395 AC: 21066 AN: 53396

Middle Eastern (MID) AF: 0.404 AC: 2333 AN: 5768

European-Non Finnish (NFE) AF: 0.385 AC: 427770 AN: 1111924

Other (OTH) AF: 0.385 AC: 23230 AN: 60384

GnomAD4 genome AF: 0.370 AC: 56315 AN: 152008 Hom.: 10510 Cov.: 31 AF XY: 0.370 AC XY: 27521 AN XY: 74300

African (AFR) AF: 0.324 AC: 13438 AN: 41468

American (AMR) AF: 0.395 AC: 6039 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2199 AN: 5150

South Asian (SAS) AF: 0.265 AC: 1275 AN: 4806

European-Finnish (FIN) AF: 0.394 AC: 4163 AN: 10568

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26322 AN: 67950

Other (OTH) AF: 0.374 AC: 790 AN: 2110

Alfa AF: 0.392 Hom.: 3821

Bravo AF: 0.375

Asia WGS AF: 0.342 AC: 1191 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.392

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 20, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 13, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pitt-Hopkins syndrome Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Corneal dystrophy, Fuchs endothelial, 3 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.7
DANN	Benign	0.49
PhyloP100		-2.1
Mutation Taster		=99/1	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: rs8766; hg19: chr18-52895531; COSMIC: COSV61901192;