rs567398278

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001083962.2(TCF4):c.223A>G(p.Thr75Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,612,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

TCF4
NM_001083962.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.76

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 links:

TCF4-AS1 (HGNC:51642): (TCF4 antisense RNA 1)

TCF4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the TCF4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 4.1035 (above the threshold of 3.09). Trascript score misZ: 4.5676 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, corneal dystrophy, Fuchs endothelial, 3, autosomal dominant non-syndromic intellectual disability, autism spectrum disorder, Fuchs' endothelial dystrophy, Pitt-Hopkins syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.04813096).

BP6

Variant 18-55461100-T-C is Benign according to our data. Variant chr18-55461100-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 160082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000131 (2/152198) while in subpopulation SAS AF= 0.000416 (2/4808). AF 95% confidence interval is 0.0000732. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2 link	c.223A>G	p.Thr75Ala	missense_variant	Exon 5 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.223A>G	p.Thr75Ala	missense_variant	Exon 5 of 20	5	NM_001083962.2	ENSP00000346440.3		P15884-3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250424

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135358

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 SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1460406

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726518

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 12, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 09, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Pitt-Hopkins syndrome

Benign:1

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.39

.;T;.;T;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;T;.;.;T;T;T;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.88

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

Benign

0.0045

MetaRNN

Benign

0.048

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.23

.;N;.;.;.;N;N;N;.;.;.;.;.;N;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.52

.;N;.;.;.;N;N;.;N;N;N;N;N;N;.;N;.;N;N;.;N;.;.;.;.;N;.;N;N;.;N

REVEL

Benign

0.19

Sift

Benign

0.64

.;T;.;.;.;T;T;.;T;T;T;T;T;T;.;T;.;T;T;.;T;.;.;.;.;T;.;T;T;.;T

Sift4G

Benign

0.55

T;T;.;.;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;T;T;T;.;.;T;T;T;.

Polyphen

0.0010, 0.087

.;B;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.44

MutPred

0.15

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of phosphorylation at T177 (P = 0.0109);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.93

MPC

0.58

ClinPred

0.089

GERP RS

6.0

Varity_R

0.044

gMVP

0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over