15-56921085-A-G

Variant names:

• chr15-56921085-A-G
• rs35615435
• NM_207037.2:c.135A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_207037.2(TCF12):​c.135A>G​(p.Gln45Gln) 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:4
• Conservation: PhyloP100: 2.32
• Publications: 7 publications found

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]

TCF12 Gene-Disease associations (from GenCC):

• TCF12-related craniosynostosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen
• hypogonadotropic hypogonadism 26 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Kallmann syndrome

  Inheritance: AD, AR Classification: STRONG Submitted by: Franklin by Genoox
• isolated brachycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated plagiocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 263277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207037.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	NM_207037.2	MANE Select	c.135A>G	p.Gln45Gln	synonymous	Exon 3 of 21	NP_996920.1
	TCF12	NM_001322151.2		c.135A>G	p.Gln45Gln	synonymous	Exon 3 of 21	NP_001309080.1
	TCF12	NM_001322159.3		c.135A>G	p.Gln45Gln	synonymous	Exon 3 of 21	NP_001309088.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	ENST00000333725.10	TSL:1 MANE Select	c.135A>G	p.Gln45Gln	synonymous	Exon 3 of 21	ENSP00000331057.6
	TCF12	ENST00000267811.9	TSL:1	c.135A>G	p.Gln45Gln	synonymous	Exon 3 of 20	ENSP00000267811.5
	TCF12	ENST00000557843.5	TSL:1	c.135A>G	p.Gln45Gln	synonymous	Exon 3 of 20	ENSP00000453737.1

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

GnomAD2 exomes AF: 0.0382 AC: 9519 AN: 248886 AF XY: 0.0360

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 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

African (AFR) AF: 0.0622 AC: 2072 AN: 33332

American (AMR) AF: 0.0265 AC: 1170 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.00584 AC: 152 AN: 26022

East Asian (EAS) AF: 0.277 AC: 10870 AN: 39276

South Asian (SAS) AF: 0.0446 AC: 3803 AN: 85340

European-Finnish (FIN) AF: 0.0157 AC: 833 AN: 53200

Middle Eastern (MID) AF: 0.00643 AC: 37 AN: 5756

European-Non Finnish (NFE) AF: 0.000849 AC: 942 AN: 1109376

Other (OTH) AF: 0.0250 AC: 1504 AN: 60132

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

African (AFR) AF: 0.0659 AC: 2736 AN: 41546

American (AMR) AF: 0.0167 AC: 256 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.288 AC: 1497 AN: 5192

South Asian (SAS) AF: 0.0541 AC: 261 AN: 4824

European-Finnish (FIN) AF: 0.0192 AC: 204 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 67990

Other (OTH) AF: 0.0247 AC: 52 AN: 2108

Alfa AF: 0.0116 Hom.: 79

Bravo AF: 0.0367

Asia WGS AF: 0.133 AC: 464 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.8
DANN	Benign	0.84
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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