15-56921085-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_207037.2(TCF12):c.135A>G(p.Gln45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,608,830 control chromosomes in the GnomAD database, including 2,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (329 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1829 hom.)
• Consequence: TCF12 NM_207037.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.32

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 15-56921085-A-G is Benign according to our data. Variant chr15-56921085-A-G is described in ClinVar as [Benign]. Clinvar id is 263277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-56921085-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF12	NM_207037.2	c.135A>G	p.Gln45=	synonymous_variant	3/21	ENST00000333725.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF12	ENST00000333725.10	c.135A>G	p.Gln45=	synonymous_variant	3/21	1	NM_207037.2	P4

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5117 AN: 152126 Hom.: 328 Cov.: 32

Gnomad AFR AF: 0.0659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.0545

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0382 AC: 9519 AN: 248886 Hom.: 898 AF XY: 0.0360 AC XY: 4847 AN XY: 134634

Gnomad AFR exome AF: 0.0664

Gnomad AMR exome AF: 0.0294

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.300

Gnomad SAS exome AF: 0.0433

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0147 AC: 21383 AN: 1456586 Hom.: 1829 Cov.: 30 AF XY: 0.0153 AC XY: 11090 AN XY: 724586

Gnomad4 AFR exome AF: 0.0622

Gnomad4 AMR exome AF: 0.0265

Gnomad4 ASJ exome AF: 0.00584

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.0446

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.000849

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome AF: 0.0336 AC: 5121 AN: 152244 Hom.: 329 Cov.: 32 AF XY: 0.0361 AC XY: 2691 AN XY: 74452

Gnomad4 AFR AF: 0.0659

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.0247

Alfa AF: 0.0111 Hom.: 61

Bravo AF: 0.0367

Asia WGS AF: 0.133 AC: 464 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	9.8
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35615435; hg19: chr15-57213283; COSMIC: COSV51006854; COSMIC: COSV51006854;