NM_207037.2:c.76-18A>G

Variant names:

• chr15-56921008-A-G
• rs75960447
• NM_207037.2:c.76-18A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207037.2(TCF12):​c.76-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,585,544 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (84 hom.)
• Consequence: TCF12 NM_207037.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.533
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-56921008-A-G is Benign according to our data. Variant chr15-56921008-A-G is described in ClinVar as Benign. ClinVar VariationId is 263283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

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.76-18A>G		intron	N/A	NP_996920.1
	TCF12	NM_001322151.2		c.76-18A>G		intron	N/A	NP_001309080.1
	TCF12	NM_001322159.3		c.76-18A>G		intron	N/A	NP_001309088.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	ENST00000333725.10	TSL:1 MANE Select	c.76-18A>G		intron	N/A	ENSP00000331057.6
	TCF12	ENST00000267811.9	TSL:1	c.76-18A>G		intron	N/A	ENSP00000267811.5
	TCF12	ENST00000557843.5	TSL:1	c.76-18A>G		intron	N/A	ENSP00000453737.1

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 681 AN: 152122 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00750

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00959

GnomAD2 exomes AF: 0.0103 AC: 2410 AN: 235026 AF XY: 0.00795

Gnomad AFR exome AF: 0.00244

Gnomad AMR exome AF: 0.0636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00861

Gnomad FIN exome AF: 0.00156

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00758

GnomAD4 exome AF: 0.00395 AC: 5667 AN: 1433306 Hom.: 84 Cov.: 28 AF XY: 0.00361 AC XY: 2573 AN XY: 712412

African (AFR) AF: 0.00248 AC: 81 AN: 32606

American (AMR) AF: 0.0558 AC: 2289 AN: 41022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.00733 AC: 283 AN: 38632

South Asian (SAS) AF: 0.000408 AC: 33 AN: 80952

European-Finnish (FIN) AF: 0.00170 AC: 89 AN: 52430

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5682

European-Non Finnish (NFE) AF: 0.00240 AC: 2629 AN: 1097522

Other (OTH) AF: 0.00440 AC: 260 AN: 59112

GnomAD4 genome AF: 0.00456 AC: 694 AN: 152238 Hom.: 8 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74442

African (AFR) AF: 0.00286 AC: 119 AN: 41536

American (AMR) AF: 0.0218 AC: 333 AN: 15300

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

East Asian (EAS) AF: 0.00752 AC: 39 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00241 AC: 164 AN: 68002

Other (OTH) AF: 0.00949 AC: 20 AN: 2108

Alfa AF: 0.00386 Hom.: 2

Bravo AF: 0.00776

Asia WGS AF: 0.00809 AC: 28 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.0
DANN	Benign	0.67
PhyloP100		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs75960447; hg19: chr15-57213206;