dbSNP rs1556050492: TCF4:p.Gly113Trp (chr18-55403486-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001083962.2(TCF4):c.337G>T(p.Gly113Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G113R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TCF4
NM_001083962.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.52

Publications

0 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: 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

TCF4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2 link	c.337G>T	p.Gly113Trp	missense_variant	Exon 6 of 20	ENST00000354452.8	NP_001077431.1	P15884-3B3KVA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8 link	c.337G>T	p.Gly113Trp	missense_variant	Exon 6 of 20	5	NM_001083962.2	ENSP00000346440.3		P15884-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 17, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

.;D;.;T;.;D;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;T;.;T;.;.;T;.;.;T;T;T;.;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;.;.;D;D;D;.;D;.;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.67

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.3

.;M;.;.;.;M;M;M;.;.;.;.;.;.;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

5.5

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-4.0

.;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.;D;.;.;.;.;D;.;D;D;.;D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

.;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.;D;.;.;.;.;D;.;D;D;.;D;D

Sift4G

Uncertain

0.0020

D;D;.;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;.;.;.;D;D;D;.;.;D;D;D;.;.

Polyphen

1.0, 1.0

.;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.82

MutPred

0.30

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.04);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.92

MPC

1.7

ClinPred

0.99

GERP RS

6.0

PromoterAI

-0.0068

Neutral

(source)

Varity_R

0.49

gMVP

0.48

Mutation Taster

=52/48

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over