15-56921093-G-A

Variant names:

• chr15-56921093-G-A
• NM_207037.2:c.143G>A

Variant summary

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

The NM_207037.2(TCF12):​c.143G>A​(p.Gly48Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TCF12 NM_207037.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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.143G>A	p.Gly48Glu	missense_variant	Exon 3 of 21	ENST00000333725.10	NP_996920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF12	ENST00000333725.10	c.143G>A	p.Gly48Glu	missense_variant	Exon 3 of 21	1	NM_207037.2	ENSP00000331057.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454846 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 723714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 27, 2023

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	0.41
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;D;T;.;D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;.;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.49	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M;.;M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;.
Vest4		0.62
MutPred		0.23		Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);
MVP		0.66
MPC		0.41
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.82
gMVP		0.46

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: chr15-57213291;