NM_207037.2:c.76-45T>C

Variant names:

• chr15-56920981-T-C
• rs76588581
• NM_207037.2:c.76-45T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_207037.2(TCF12):​c.76-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,481,844 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (54 hom.)
• Consequence: TCF12 NM_207037.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.721
• Publications: 1 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, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• hypogonadotropic hypogonadism 26 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 15-56920981-T-C is Benign according to our data. Variant chr15-56920981-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1192812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0127 (1935/152276) while in subpopulation AFR AF = 0.0402 (1670/41548). AF 95% confidence interval is 0.0386. There are 46 homozygotes in GnomAd4. There are 877 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	NM_207037.2	MANE Select	c.76-45T>C		intron	N/A	NP_996920.1	Q99081-3
	TCF12	NM_001322151.2		c.76-45T>C		intron	N/A	NP_001309080.1	Q99081-3
	TCF12	NM_001322159.3		c.76-45T>C		intron	N/A	NP_001309088.1	Q99081-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	ENST00000333725.10	TSL:1 MANE Select	c.76-45T>C		intron	N/A	ENSP00000331057.6	Q99081-3
	TCF12	ENST00000267811.9	TSL:1	c.76-45T>C		intron	N/A	ENSP00000267811.5	Q99081-1
	TCF12	ENST00000557843.5	TSL:1	c.76-45T>C		intron	N/A	ENSP00000453737.1	Q99081-1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1916 AN: 152160 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00531 AC: 1067 AN: 201024 AF XY: 0.00438

Gnomad AFR exome AF: 0.0394

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000603

Gnomad OTH exome AF: 0.00552

GnomAD4 exome AF: 0.00235 AC: 3131 AN: 1329568 Hom.: 54 Cov.: 18 AF XY: 0.00230 AC XY: 1513 AN XY: 657824

African (AFR) AF: 0.0411 AC: 1220 AN: 29670

American (AMR) AF: 0.00233 AC: 77 AN: 33042

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 1130 AN: 22852

East Asian (EAS) AF: 0.00 AC: 0 AN: 36926

South Asian (SAS) AF: 0.000111 AC: 8 AN: 72220

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50398

Middle Eastern (MID) AF: 0.00653 AC: 35 AN: 5362

European-Non Finnish (NFE) AF: 0.000336 AC: 344 AN: 1024388

Other (OTH) AF: 0.00578 AC: 316 AN: 54710

GnomAD4 genome AF: 0.0127 AC: 1935 AN: 152276 Hom.: 46 Cov.: 32 AF XY: 0.0118 AC XY: 877 AN XY: 74460

African (AFR) AF: 0.0402 AC: 1670 AN: 41548

American (AMR) AF: 0.00340 AC: 52 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 148 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 68002

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0103 Hom.: 9

Bravo AF: 0.0143

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.2
DANN	Benign	0.87
PhyloP100		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs76588581; hg19: chr15-57213179;