rs12442879

Positions:

• chr15-57232784-G-A
• chr15-57232784-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000333725.10(TCF12):​c.898G>A​(p.Gly300Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,612,244 control chromosomes in the GnomAD database, including 3,004 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.040 (374 hom., cov: 31)
  • Exomes 𝑓: 0.039 (2630 hom.)
• Consequence: TCF12 ENST00000333725.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015925467).
• BP6: Variant 15-57232784-G-A is Benign according to our data. Variant chr15-57232784-G-A is described in ClinVar as [Benign]. Clinvar id is 263284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-57232784-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF12	NM_207037.2	c.898G>A	p.Gly300Ser	missense_variant	11/21	ENST00000333725.10	NP_996920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF12	ENST00000333725.10	c.898G>A	p.Gly300Ser	missense_variant	11/21	1	NM_207037.2	ENSP00000331057	P4

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 6086 AN: 151674 Hom.: 370 Cov.: 31

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0936

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0278

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0484

GnomAD3 exomes AF: 0.0628 AC: 15703 AN: 250048 Hom.: 1570 AF XY: 0.0538 AC XY: 7283 AN XY: 135270

Gnomad AFR exome AF: 0.00923

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.0263

Gnomad EAS exome AF: 0.00225

Gnomad SAS exome AF: 0.0290

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0344

Gnomad OTH exome AF: 0.0557

GnomAD4 exome AF: 0.0391 AC: 57090 AN: 1460460 Hom.: 2630 Cov.: 32 AF XY: 0.0377 AC XY: 27376 AN XY: 726568

Gnomad4 AFR exome AF: 0.00740

Gnomad4 AMR exome AF: 0.265

Gnomad4 ASJ exome AF: 0.0268

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.0301

Gnomad4 FIN exome AF: 0.0407

Gnomad4 NFE exome AF: 0.0335

Gnomad4 OTH exome AF: 0.0367

GnomAD4 genome AF: 0.0402 AC: 6104 AN: 151784 Hom.: 374 Cov.: 31 AF XY: 0.0417 AC XY: 3094 AN XY: 74188

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.0283

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0277

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.0343

Gnomad4 OTH AF: 0.0493

Alfa AF: 0.0347 Hom.: 429

Bravo AF: 0.0505

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.0112 AC: 49

ESP6500EA AF: 0.0332 AC: 285

ExAC AF: 0.0542 AC: 6581

Asia WGS AF: 0.0370 AC: 129 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2018	This variant is associated with the following publications: (PMID: 26264438) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.15	.;T;T;.;T;T;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.87
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	.;.;T;T;T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;.;N;N;.;.;.
MutationTaster	Benign	0.036	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.44	T;T;T;T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;P;.;B;P;P;.;D
Vest4		0.057
MPC		0.11
ClinPred		0.0097	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.37

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: rs12442879; hg19: chr15-57524982;