chr15-56949459-A-C

Variant names:

• chr15-56949459-A-C
• rs213168
• NM_207037.2:c.148+28361A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_207037.2(TCF12):​c.148+28361A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,228 control chromosomes in the GnomAD database, including 3,779 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3779 hom., cov: 33)
• Consequence: TCF12 NM_207037.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF12	NM_207037.2	c.148+28361A>C		intron_variant	Intron 3 of 20	ENST00000333725.10	NP_996920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF12	ENST00000333725.10	c.148+28361A>C		intron_variant	Intron 3 of 20	1	NM_207037.2	ENSP00000331057.6

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33527 AN: 152110 Hom.: 3771 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.229

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.220 AC: 33557 AN: 152228 Hom.: 3779 Cov.: 33 AF XY: 0.218 AC XY: 16226 AN XY: 74424

African (AFR) AF: 0.199 AC: 8256 AN: 41540

American (AMR) AF: 0.225 AC: 3438 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3472

East Asian (EAS) AF: 0.187 AC: 967 AN: 5182

South Asian (SAS) AF: 0.196 AC: 947 AN: 4824

European-Finnish (FIN) AF: 0.219 AC: 2316 AN: 10578

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16273 AN: 68020

Other (OTH) AF: 0.229 AC: 485 AN: 2116

Alfa AF: 0.228 Hom.: 541

Bravo AF: 0.219

Asia WGS AF: 0.190 AC: 660 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.6
DANN	Benign	0.81
PhyloP100		1.1
Mutation Taster		=100/0	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: rs213168; hg19: chr15-57241657;