rs532294589

Variant summary

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

The NM_001083962.2(TCF4):​c.240G>A​(p.Met80Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,613,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TCF4
NM_001083962.2 missense

Scores

1
7
11

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TCF4. . Gene score misZ 4.1035 (greater than the threshold 3.09). Trascript score misZ 4.5676 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.020418197).
BP6
Variant 18-55461083-C-T is Benign according to our data. Variant chr18-55461083-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 468956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000525 (8/152254) while in subpopulation EAS AF= 0.00154 (8/5190). AF 95% confidence interval is 0.000767. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TCF4NM_001083962.2 linkuse as main transcriptc.240G>A p.Met80Ile missense_variant 5/20 ENST00000354452.8 NP_001077431.1 P15884-3B3KVA4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TCF4ENST00000354452.8 linkuse as main transcriptc.240G>A p.Met80Ile missense_variant 5/205 NM_001083962.2 ENSP00000346440.3 P15884-3

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152136
Hom.:
0
Cov.:
32
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:
0.00154
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000199
AC:
50
AN:
250674
Hom.:
0
AF XY:
0.000185
AC XY:
25
AN XY:
135478
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00273
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000294
AC:
43
AN:
1460982
Hom.:
0
Cov.:
30
AF XY:
0.0000234
AC XY:
17
AN XY:
726770
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00103
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00154
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000422
Hom.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.000222
AC:
27
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pitt-Hopkins syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 02, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
.;T;.;T;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;T;.;.;T;T;T;.;.;T
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Pathogenic
0.98
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
Benign
0.011
T
MetaRNN
Benign
0.010
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;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
.;L;.;.;.;L;L;L;.;.;.;.;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-0.27
.;N;.;.;.;N;N;.;N;N;N;N;N;N;.;N;.;N;N;.;N;.;.;.;.;N;.;N;N;.;N;N
REVEL
Benign
0.19
Sift
Benign
0.079
.;T;.;.;.;T;T;.;T;D;T;T;T;T;.;T;.;T;D;.;D;.;.;.;.;D;.;D;D;.;D;D
Sift4G
Benign
0.39
T;T;.;.;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;T;T;T;.;.;T;D;T;.;.
Polyphen
0.018, 0.12
.;B;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.66
MutPred
0.15
.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at L187 (P = 0.0203);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.65
MPC
0.71
ClinPred
0.060
T
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.17
gMVP
0.20

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.

Other links and lift over

dbSNP: rs532294589; hg19: chr18-53128314; API