rs114409025

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-56919800-C-G
• chr15-56919800-C-T

Variant summary

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

The NM_001322164.2(TCF12):​c.-114C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,166,340 control chromosomes in the GnomAD database, including 91 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 (47 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (44 hom.)
• Consequence: TCF12 NM_001322164.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-56919800-C-G is Benign according to our data. Variant chr15-56919800-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1186674.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 (1939/152178) while in subpopulation AFR AF = 0.0404 (1677/41528). AF 95% confidence interval is 0.0388. There are 47 homozygotes in GnomAd4. There are 888 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AD,AR gene

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>G		intron	N/A	NP_996920.1	Q99081-3
	TCF12	NM_001322164.2		c.-114C>G		5_prime_UTR	Exon 1 of 20	NP_001309093.1
	TCF12	NM_001322165.2		c.-114C>G		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>G		intron	N/A	ENSP00000331057.6	Q99081-3
	TCF12	ENST00000267811.9	TSL:1	c.-22-92C>G		intron	N/A	ENSP00000267811.5	Q99081-1
	TCF12	ENST00000557843.5	TSL:1	c.-12-102C>G		intron	N/A	ENSP00000453737.1	Q99081-1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1920 AN: 152062 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00256 AC: 2592 AN: 1014162 Hom.: 44 Cov.: 12 AF XY: 0.00248 AC XY: 1277 AN XY: 514164

African (AFR) AF: 0.0407 AC: 944 AN: 23192

American (AMR) AF: 0.00302 AC: 87 AN: 28824

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 1018 AN: 20456

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

South Asian (SAS) AF: 0.000117 AC: 8 AN: 68516

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

Middle Eastern (MID) AF: 0.00601 AC: 22 AN: 3658

European-Non Finnish (NFE) AF: 0.000337 AC: 252 AN: 747692

Other (OTH) AF: 0.00588 AC: 261 AN: 44352

GnomAD4 genome AF: 0.0127 AC: 1939 AN: 152178 Hom.: 47 Cov.: 31 AF XY: 0.0119 AC XY: 888 AN XY: 74394

African (AFR) AF: 0.0404 AC: 1677 AN: 41528

American (AMR) AF: 0.00333 AC: 51 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67990

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

Alfa AF: 0.00324 Hom.: 0

Bravo AF: 0.0145

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.80
CADD	Benign	1.6
DANN	Benign	0.85
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs114409025; hg19: chr15-57211998;