15-57273234-C-T

Variant names:

• chr15-57273234-C-T
• rs77034126
• NM_207037.2:c.1950C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_207037.2(TCF12):​c.1950C>T​(p.Val650Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,614,126 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (37 hom.)
• Consequence: TCF12 NM_207037.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.71

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 15-57273234-C-T is Benign according to our data. Variant chr15-57273234-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00432 (658/152294) while in subpopulation AMR AF= 0.00994 (152/15296). AF 95% confidence interval is 0.00865. There are 3 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 658 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF12	NM_207037.2	c.1950C>T	p.Val650Val	synonymous_variant	Exon 19 of 21	ENST00000333725.10	NP_996920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF12	ENST00000333725.10	c.1950C>T	p.Val650Val	synonymous_variant	Exon 19 of 21	1	NM_207037.2	ENSP00000331057.6

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 658 AN: 152176 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00611

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00382 AC: 960 AN: 251328 Hom.: 9 AF XY: 0.00364 AC XY: 495 AN XY: 135826

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00551 AC: 8054 AN: 1461832 Hom.: 37 Cov.: 31 AF XY: 0.00538 AC XY: 3913 AN XY: 727202

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00512

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.00655

Gnomad4 OTH exome AF: 0.00518

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152294 Hom.: 3 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74468

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00611

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00501 Hom.: 5

Bravo AF: 0.00466

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Apr 27, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TCF12: BP4, BS2 -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

TCF12-related craniosynostosis;C5676903:Hypogonadotropic hypogonadism 26 with or without anosmia Benign:1

Sep 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.6
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs77034126; hg19: chr15-57565432;