chr15-57231140-T-C

Variant names:

• chr15-57231140-T-C
• rs117914532
• NM_207037.2:c.580-12T>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_207036.2(TCF12):​c.580-12T>C variant causes a intron change. The variant allele was found at a frequency of 0.00867 in 1,581,168 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (62 hom.)
• Consequence: TCF12 NM_207036.2 intron
• Scores: Splicing: ADA: 0.009539
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.94
• 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: 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=-0.56).
• BP6: Variant 15-57231140-T-C is Benign according to our data. Variant chr15-57231140-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0079 (1202/152224) while in subpopulation NFE AF = 0.0108 (732/67970). AF 95% confidence interval is 0.0101. There are 7 homozygotes in GnomAd4. There are 626 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207036.2. 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.580-12T>C		intron	N/A	NP_996920.1
	TCF12	NM_001322151.2		c.580-12T>C		intron	N/A	NP_001309080.1
	TCF12	NM_001322159.3		c.580-12T>C		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.580-12T>C		intron	N/A	ENSP00000331057.6
	TCF12	ENST00000267811.9	TSL:1	c.580-12T>C		intron	N/A	ENSP00000267811.5
	TCF12	ENST00000557843.5	TSL:1	c.580-12T>C		intron	N/A	ENSP00000453737.1

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1203 AN: 152106 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00571

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00748 AC: 1874 AN: 250584 AF XY: 0.00738

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00769

GnomAD4 exome AF: 0.00875 AC: 12502 AN: 1428944 Hom.: 62 Cov.: 25 AF XY: 0.00849 AC XY: 6054 AN XY: 712938

African (AFR) AF: 0.00137 AC: 45 AN: 32778

American (AMR) AF: 0.00235 AC: 105 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 97 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39426

South Asian (SAS) AF: 0.000187 AC: 16 AN: 85454

European-Finnish (FIN) AF: 0.0245 AC: 1300 AN: 52980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00974 AC: 10542 AN: 1082796

Other (OTH) AF: 0.00670 AC: 397 AN: 59288

GnomAD4 genome AF: 0.00790 AC: 1202 AN: 152224 Hom.: 7 Cov.: 32 AF XY: 0.00841 AC XY: 626 AN XY: 74412

African (AFR) AF: 0.00156 AC: 65 AN: 41566

American (AMR) AF: 0.00570 AC: 87 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0277 AC: 294 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0108 AC: 732 AN: 67970

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00871 Hom.: 0

Bravo AF: 0.00614

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.78
PhyloP100		4.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0095
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.010		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: rs117914532; hg19: chr15-57523338;