15-57232784-G-T

Variant names:

• chr15-57232784-G-T
• rs12442879
• NM_207037.2:c.898G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_207037.2(TCF12):​c.898G>T​(p.Gly300Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G300S) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: TCF12 NM_207037.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 22 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42113686).

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.898G>T	p.Gly300Cys	missense	Exon 11 of 21	NP_996920.1
	TCF12	NM_001322151.2		c.898G>T	p.Gly300Cys	missense	Exon 11 of 21	NP_001309080.1
	TCF12	NM_001322159.3		c.898G>T	p.Gly300Cys	missense	Exon 11 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.898G>T	p.Gly300Cys	missense	Exon 11 of 21	ENSP00000331057.6
	TCF12	ENST00000267811.9	TSL:1	c.898G>T	p.Gly300Cys	missense	Exon 11 of 20	ENSP00000267811.5
	TCF12	ENST00000557843.5	TSL:1	c.898G>T	p.Gly300Cys	missense	Exon 11 of 20	ENSP00000453737.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151684 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151684 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74072

African (AFR) AF: 0.0000242 AC: 1 AN: 41264

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 695

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.4
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.91	P
Vest4		0.50
MutPred		0.35		Loss of glycosylation at S297 (P = 0.0902)
MVP		0.68
MPC		0.50
ClinPred		0.99	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.57
Mutation Taster		=90/10	polymorphism

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: rs12442879; hg19: chr15-57524982;