15-56919800-C-T

Variant names:

• chr15-56919800-C-T
• rs114409025
• NM_207037.2:c.-22-92C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001322164.2(TCF12):​c.-114C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000171 in 1,166,270 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.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: TCF12 NM_001322164.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.951
• Publications: 0 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hypogonadotropic hypogonadism 26 with or without anosmia

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

  Inheritance: AR, AD 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322164.2. 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.-22-92C>T		intron	N/A	NP_996920.1	Q99081-3
	TCF12	NM_001322164.2		c.-114C>T		5_prime_UTR	Exon 1 of 20	NP_001309093.1
	TCF12	NM_001322165.2		c.-114C>T		5_prime_UTR	Exon 1 of 19	NP_001309094.1	Q99081-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	ENST00000333725.10	TSL:1 MANE Select	c.-22-92C>T		intron	N/A	ENSP00000331057.6	Q99081-3
	TCF12	ENST00000267811.9	TSL:1	c.-22-92C>T		intron	N/A	ENSP00000267811.5	Q99081-1
	TCF12	ENST00000557843.5	TSL:1	c.-12-102C>T		intron	N/A	ENSP00000453737.1	Q99081-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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 AF: 9.86e-7 AC: 1 AN: 1014198 Hom.: 0 Cov.: 12 AF XY: 0.00000194 AC XY: 1 AN XY: 514184

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23212

American (AMR) AF: 0.00 AC: 0 AN: 28824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20460

East Asian (EAS) AF: 0.00 AC: 0 AN: 33336

South Asian (SAS) AF: 0.00 AC: 0 AN: 68516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3662

European-Non Finnish (NFE) AF: 0.00000134 AC: 1 AN: 747696

Other (OTH) AF: 0.00 AC: 0 AN: 44356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74270

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.0
DANN	Benign	0.94
PhyloP100		-0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs114409025; hg19: chr15-57211998;