15-57143728-A-G

Variant names:

• chr15-57143728-A-G
• rs2733333
• NM_207037.2:c.326-22674A>G

Variant summary

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

The NM_207036.2(TCF12):​c.326-22674A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 152,056 control chromosomes in the GnomAD database, including 42,719 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 0.74 (42719 hom., cov: 31)
• Consequence: TCF12 NM_207036.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 6 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207036.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	NM_207037.2	MANE Select	c.326-22674A>G		intron	N/A	NP_996920.1
	TCF12	NM_001322151.2		c.326-22674A>G		intron	N/A	NP_001309080.1
	TCF12	NM_001322159.3		c.326-22674A>G		intron	N/A	NP_001309088.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	ENST00000333725.10	TSL:1 MANE Select	c.326-22674A>G		intron	N/A	ENSP00000331057.6
	TCF12	ENST00000267811.9	TSL:1	c.326-22674A>G		intron	N/A	ENSP00000267811.5
	TCF12	ENST00000557843.5	TSL:1	c.326-22674A>G		intron	N/A	ENSP00000453737.1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112460 AN: 151938 Hom.: 42698 Cov.: 31

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.822

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.755

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

GnomAD4 genome AF: 0.740 AC: 112515 AN: 152056 Hom.: 42719 Cov.: 31 AF XY: 0.740 AC XY: 55005 AN XY: 74344

African (AFR) AF: 0.566 AC: 23462 AN: 41424

American (AMR) AF: 0.822 AC: 12568 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2357 AN: 3468

East Asian (EAS) AF: 0.604 AC: 3120 AN: 5162

South Asian (SAS) AF: 0.704 AC: 3394 AN: 4822

European-Finnish (FIN) AF: 0.844 AC: 8923 AN: 10578

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.827 AC: 56206 AN: 67988

Other (OTH) AF: 0.756 AC: 1599 AN: 2116

Alfa AF: 0.792 Hom.: 87451

Bravo AF: 0.731

Asia WGS AF: 0.676 AC: 2350 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.29
DANN	Benign	0.64
PhyloP100		-1.7
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: rs2733333; hg19: chr15-57435926;