rs36060670

Positions:

• chr15-57262146-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_207037.2(TCF12):​c.1520T>G​(p.Leu507Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000584 in 1,613,768 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (6 hom.)
• Consequence: TCF12 NM_207037.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.76

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=0.007063508).
• BP6: Variant 15-57262146-T-G is Benign according to our data. Variant chr15-57262146-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 376986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00259 (394/152298) while in subpopulation AFR AF= 0.00864 (359/41562). AF 95% confidence interval is 0.0079. There are 2 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 394 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF12	NM_207037.2	c.1520T>G	p.Leu507Arg	missense_variant	17/21	ENST00000333725.10	NP_996920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF12	ENST00000333725.10	c.1520T>G	p.Leu507Arg	missense_variant	17/21	1	NM_207037.2	ENSP00000331057	P4

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00864

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000781 AC: 196 AN: 250936 Hom.: 1 AF XY: 0.000553 AC XY: 75 AN XY: 135618

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000376 AC: 549 AN: 1461470 Hom.: 6 Cov.: 30 AF XY: 0.000342 AC XY: 249 AN XY: 727014

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00252 AC XY: 188 AN XY: 74490

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.00328

ESP6500AA AF: 0.0119 AC: 52

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2021	Observed in 0.0999% (282/282330 alleles) in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25271085) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;T;.;D;T;.;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0071	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	.;M;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.4	D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;D;T
Polyphen		0.38	B;P;D;B;P;D;.;B;D;.
Vest4		0.93
MVP		0.33
MPC		0.66
ClinPred		0.014	T
GERP RS		5.9
Varity_R		0.53
gMVP		0.54

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: rs36060670; hg19: chr15-57554344;