15-57232805-T-C

Variant names:

• chr15-57232805-T-C
• rs1555403191
• NM_207037.2:c.919T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_207037.2(TCF12):​c.919T>C​(p.Tyr307His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TCF12 NM_207037.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF12	NM_207037.2	c.919T>C	p.Tyr307His	missense_variant	Exon 11 of 21	ENST00000333725.10	NP_996920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF12	ENST00000333725.10	c.919T>C	p.Tyr307His	missense_variant	Exon 11 of 21	1	NM_207037.2	ENSP00000331057.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 26, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	.;D;T;.;D;T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.6	M;M;.;M;M;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D
Sift4G	Benign	0.37	T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;.;D;D;D;.;D
Vest4		0.56
MutPred		0.27		.;.;Loss of phosphorylation at Y303 (P = 0.0105);.;.;.;.;.;
MVP		0.35
MPC		0.59
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.72

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

Other links and lift over

dbSNP: rs1555403191; hg19: chr15-57525003;