rs17819994

Variant names:

• chr15-57197836-A-G
• rs17819994
• NM_207037.2:c.579+11A>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.579+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,612,982 control chromosomes in the GnomAD database, including 3,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (376 hom., cov: 32)
  • Exomes 𝑓: 0.039 (2636 hom.)
• Consequence: TCF12 NM_207037.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.540
• Publications: 3 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=-0.89).
• BP6: Variant 15-57197836-A-G is Benign according to our data. Variant chr15-57197836-A-G is described in ClinVar as Benign. ClinVar VariationId is 263281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 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.579+11A>G		intron	N/A	NP_996920.1
	TCF12	NM_001322151.2		c.579+11A>G		intron	N/A	NP_001309080.1
	TCF12	NM_001322159.3		c.579+11A>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.579+11A>G		intron	N/A	ENSP00000331057.6
	TCF12	ENST00000267811.9	TSL:1	c.579+11A>G		intron	N/A	ENSP00000267811.5
	TCF12	ENST00000557843.5	TSL:1	c.579+11A>G		intron	N/A	ENSP00000453737.1

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6121 AN: 152106 Hom.: 372 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0632 AC: 15824 AN: 250378 AF XY: 0.0542

Gnomad AFR exome AF: 0.00942

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.00207

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0346

Gnomad OTH exome AF: 0.0569

GnomAD4 exome AF: 0.0391 AC: 57128 AN: 1460760 Hom.: 2636 Cov.: 30 AF XY: 0.0377 AC XY: 27396 AN XY: 726640

African (AFR) AF: 0.00742 AC: 248 AN: 33438

American (AMR) AF: 0.266 AC: 11839 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 699 AN: 26112

East Asian (EAS) AF: 0.000958 AC: 38 AN: 39652

South Asian (SAS) AF: 0.0303 AC: 2607 AN: 85992

European-Finnish (FIN) AF: 0.0407 AC: 2176 AN: 53412

Middle Eastern (MID) AF: 0.0167 AC: 96 AN: 5762

European-Non Finnish (NFE) AF: 0.0335 AC: 37214 AN: 1111498

Other (OTH) AF: 0.0366 AC: 2211 AN: 60354

GnomAD4 genome AF: 0.0403 AC: 6137 AN: 152222 Hom.: 376 Cov.: 32 AF XY: 0.0419 AC XY: 3117 AN XY: 74442

African (AFR) AF: 0.0111 AC: 459 AN: 41534

American (AMR) AF: 0.168 AC: 2561 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 100 AN: 3464

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5186

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4826

European-Finnish (FIN) AF: 0.0324 AC: 344 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0344 AC: 2337 AN: 68006

Other (OTH) AF: 0.0483 AC: 102 AN: 2112

Alfa AF: 0.0384 Hom.: 124

Bravo AF: 0.0506

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.39
DANN	Benign	0.53
PhyloP100		-0.54
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: rs17819994; hg19: chr15-57490034;