chr19-1611753-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_003200.5(TCF3):c.1919C>T(p.Pro640Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,728 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
TCF3
NM_003200.5 missense
NM_003200.5 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 3.92
Genes affected
TCF3 (HGNC:11633): (transcription factor 3) This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development. Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1), childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.19353408).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCF3 | NM_003200.5 | c.1919C>T | p.Pro640Leu | missense_variant | 19/19 | ENST00000262965.12 | |
TCF3 | NM_001136139.4 | c.1910C>T | p.Pro637Leu | missense_variant | 19/20 | ENST00000588136.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCF3 | ENST00000262965.12 | c.1919C>T | p.Pro640Leu | missense_variant | 19/19 | 1 | NM_003200.5 | A1 | |
TCF3 | ENST00000588136.7 | c.1910C>T | p.Pro637Leu | missense_variant | 19/20 | 2 | NM_001136139.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461638Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727134
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74298
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2023 | This sequence change replaces proline with leucine at codon 640 of the TCF3 protein (p.Pro640Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TCF3 protein function. ClinVar contains an entry for this variant (Variation ID: 1923883). This variant has not been reported in the literature in individuals affected with TCF3-related conditions. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
T;T;T;T;T;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;L;.;.;.;.;.
MutationTaster
Benign
D;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;.;.;.;.;N
REVEL
Benign
Sift
Benign
D;.;.;.;.;.;.;.;D
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
B;.;.;B;.;.;.;B;.
Vest4
MutPred
0.28
.;.;.;.;.;.;.;.;Loss of disorder (P = 0.092);
MVP
MPC
ClinPred
D
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