dbSNP rs8766: TCF4:p.Ser647Ser (chr18-55228300-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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 (★★). The gene TCF4 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.37 ( 10510 hom., cov: 31)

Exomes 𝑓: 0.38 ( 105288 hom. )

Consequence

TCF4
NM_001083962.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -2.06

Publications

36 publications found

Variant links:

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: G2P, PanelApp Australia, Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
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

TCF4 links:

Genome browser will be placed here

ACMG classification

Specifications for TCF4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

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

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	P15884-3
TCF4	NM_001243226.3		c.2247A>G	p.Ser749Ser	synonymous	Exon 20 of 21	NP_001230155.2	E9PH57
TCF4	NM_001243228.2		c.1959A>G	p.Ser653Ser	synonymous	Exon 19 of 20	NP_001230157.1	H3BTP3

Ensembl Transcripts

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	P15884-3
TCF4	ENST00000398339.5	TSL:1	c.2247A>G	p.Ser749Ser	synonymous	Exon 20 of 21	ENSP00000381382.1	E9PH57
TCF4	ENST00000356073.8	TSL:1	c.1929A>G	p.Ser643Ser	synonymous	Exon 19 of 20	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes

AF:

0.371

AC:

56295

AN:

151890

Hom.:

10500

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.376

AC XY:

273634

AN XY:

727182

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

19849

39698

59546

79395

99244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13320

26640

39960

53280

66600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.370

AC:

56315

AN:

152008

Hom.:

10510

Cov.:

AF XY:

0.370

AC XY:

27521

AN XY:

74300

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1836

3672

5507

7343

9179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

546

1092

1638

2184

2730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Pitt-Hopkins syndrome (3)

not provided (2)

Corneal dystrophy, Fuchs endothelial, 3 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.7

(source)

DANN

Benign

0.49

PhyloP100

-2.1

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over