15-57273122-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_207037.2(TCF12):​c.1838G>T​(p.Arg613Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. R613H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TCF12
NM_207037.2 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.87
Variant links:
Genes affected
TCF12 (HGNC:11623): (transcription factor 12) The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH) E-protein family that recognizes the consensus binding site (E-box) CANNTG. This encoded protein is expressed in many tissues, among them skeletal muscle, thymus, B- and T-cells, and may participate in regulating lineage-specific gene expression through the formation of heterodimers with other bHLH E-proteins. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-57273122-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCF12NM_207037.2 linkc.1838G>T p.Arg613Leu missense_variant Exon 19 of 21 ENST00000333725.10 NP_996920.1 Q99081-3A0A024R5Z0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCF12ENST00000333725.10 linkc.1838G>T p.Arg613Leu missense_variant Exon 19 of 21 1 NM_207037.2 ENSP00000331057.6 Q99081-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Apr 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 613 of the TCF12 protein (p.Arg613Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with craniosynostosis (Invitae). 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 expected to disrupt TCF12 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg613 amino acid residue in TCF12. Other variant(s) that disrupt this residue have been observed in individuals with TCF12-related conditions (PMID: 24736737), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
.;D;D;.;D;D;.;.;D;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
.;.;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.4
.;M;.;.;M;.;.;.;.;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-6.7
D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;.;D;D;.
Vest4
0.94
MutPred
0.79
.;.;Loss of methylation at R605 (P = 0.0886);.;.;.;.;.;.;.;
MVP
0.99
MPC
2.2
ClinPred
1.0
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-57565320; COSMIC: COSV99032766; API