rs1820996

Variant names:

• chr15-57041011-T-G
• rs1820996
• NM_207037.2:c.149-22739T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_207037.2(TCF12):​c.149-22739T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,190 control chromosomes in the GnomAD database, including 3,013 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3013 hom., cov: 32)
• Consequence: TCF12 NM_207037.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF12	NM_207037.2	c.149-22739T>G		intron_variant	Intron 3 of 20	ENST00000333725.10	NP_996920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF12	ENST00000333725.10	c.149-22739T>G		intron_variant	Intron 3 of 20	1	NM_207037.2	ENSP00000331057.6

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27653 AN: 152072 Hom.: 3016 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.192

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.182 AC: 27653 AN: 152190 Hom.: 3013 Cov.: 32 AF XY: 0.181 AC XY: 13479 AN XY: 74408

African (AFR) AF: 0.0622 AC: 2585 AN: 41542

American (AMR) AF: 0.213 AC: 3261 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3468

East Asian (EAS) AF: 0.187 AC: 968 AN: 5180

South Asian (SAS) AF: 0.203 AC: 980 AN: 4828

European-Finnish (FIN) AF: 0.222 AC: 2352 AN: 10584

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16342 AN: 67978

Other (OTH) AF: 0.193 AC: 407 AN: 2114

Alfa AF: 0.201 Hom.: 457

Bravo AF: 0.174

Asia WGS AF: 0.179 AC: 623 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.48
PhyloP100		0.58
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: rs1820996; hg19: chr15-57333209;