rs532294589
Positions:
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
NM_001083962.2 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 4.42
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]
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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 |
---|---|---|---|---|---|---|---|---|
TCF4 | NM_001083962.2 | c.240G>A | p.Met80Ile | missense_variant | 5/20 | ENST00000354452.8 | NP_001077431.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TCF4 | ENST00000354452.8 | c.240G>A | p.Met80Ile | missense_variant | 5/20 | 5 | NM_001083962.2 | ENSP00000346440.3 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000199 AC: 50AN: 250674Hom.: 0 AF XY: 0.000185 AC XY: 25AN XY: 135478
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1460982Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17AN XY: 726770
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GnomAD4 genome AF: 0.0000525 AC: 8AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74456
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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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2018 | This 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
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;T;.;T;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;T;.;.;T;T;T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
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
T
MetaRNN
Benign
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
T
MutationAssessor
Benign
.;L;.;.;.;L;L;L;.;.;.;.;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.;.;.;N;N;.;N;N;N;N;N;N;.;N;.;N;N;.;N;.;.;.;.;N;.;N;N;.;N;N
REVEL
Benign
Sift
Benign
.;T;.;.;.;T;T;.;T;D;T;T;T;T;.;T;.;T;D;.;D;.;.;.;.;D;.;D;D;.;D;D
Sift4G
Benign
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
MutPred
0.15
.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at L187 (P = 0.0203);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP
MPC
0.71
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at