Genetic Variant TCF4:p.Ala664Thr (chr18-55228251-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BA1BP4BS2BP5

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Ala664Thr variant in TCF4 in gnomAD v4.1 is 0.007675 in the Amish population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Ala664Thr variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Ala664Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Ala664Thr variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Ala664Thr variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5). (TCF4 specification v.3; approved on 8/30/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA319091/MONDO:0012589/032

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

TCF4
NM_001083962.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 2.23

Publications

9 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 -14 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

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.1990G>A	p.Ala664Thr	missense	Exon 19 of 20	NP_001077431.1	P15884-3
TCF4	NM_001243226.3		c.2296G>A	p.Ala766Thr	missense	Exon 20 of 21	NP_001230155.2	E9PH57
TCF4	NM_001243228.2		c.2008G>A	p.Ala670Thr	missense	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.1990G>A	p.Ala664Thr	missense	Exon 19 of 20	ENSP00000346440.3	P15884-3
TCF4	ENST00000398339.5	TSL:1	c.2296G>A	p.Ala766Thr	missense	Exon 20 of 21	ENSP00000381382.1	E9PH57
TCF4	ENST00000356073.8	TSL:1	c.1978G>A	p.Ala660Thr	missense	Exon 19 of 20	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251390

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1111994

Other (OTH)

AF:

0.0000662

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000723

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.552

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pitt-Hopkins syndrome (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0097

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0078

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

2.2

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.44

REVEL

Benign

0.019

Sift

Benign

0.57

Sift4G

Benign

0.69

Polyphen

0.0020

Vest4

0.19

MutPred

0.23

Gain of phosphorylation at A766 (P = 0.0207)

MVP

0.24

MPC

1.2

ClinPred

0.23

GERP RS

4.9

Varity_R

0.038

gMVP

0.49

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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