NM_207037.2:c.75+62_75+65delGTTT

Variant names:

• chr15-56920030-TTTTG-T
• rs527665020
• NM_207037.2:c.75+62_75+65delGTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_207037.2(TCF12):​c.75+62_75+65delGTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,605,228 control chromosomes in the GnomAD database, including 1,417 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (71 hom., cov: 30)
  • Exomes 𝑓: 0.039 (1346 hom.)
• Consequence: TCF12 NM_207037.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.54
• 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, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• hypogonadotropic hypogonadism 26 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -10 ACMG points.

• BP6: Variant 15-56920030-TTTTG-T is Benign according to our data. Variant chr15-56920030-TTTTG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1326658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0282 (4283/151920) while in subpopulation NFE AF = 0.0441 (2995/67914). AF 95% confidence interval is 0.0428. There are 71 homozygotes in GnomAd4. There are 2008 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 71 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	NM_207037.2	MANE Select	c.75+62_75+65delGTTT		intron	N/A	NP_996920.1	Q99081-3
	TCF12	NM_001322151.2		c.75+62_75+65delGTTT		intron	N/A	NP_001309080.1	Q99081-3
	TCF12	NM_001322159.3		c.75+62_75+65delGTTT		intron	N/A	NP_001309088.1	Q99081-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF12	ENST00000333725.10	TSL:1 MANE Select	c.75+43_75+46delTTTG		intron	N/A	ENSP00000331057.6	Q99081-3
	TCF12	ENST00000267811.9	TSL:1	c.75+43_75+46delTTTG		intron	N/A	ENSP00000267811.5	Q99081-1
	TCF12	ENST00000557843.5	TSL:1	c.75+43_75+46delTTTG		intron	N/A	ENSP00000453737.1	Q99081-1

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4281 AN: 151802 Hom.: 71 Cov.: 30

Gnomad AFR AF: 0.00786

Gnomad AMI AF: 0.0837

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0441

Gnomad OTH AF: 0.0197

GnomAD2 exomes AF: 0.0271 AC: 6691 AN: 246558 AF XY: 0.0277

Gnomad AFR exome AF: 0.00785

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.00188

Gnomad FIN exome AF: 0.0236

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0292

GnomAD4 exome AF: 0.0390 AC: 56612 AN: 1453308 Hom.: 1346 AF XY: 0.0387 AC XY: 27967 AN XY: 723396

African (AFR) AF: 0.00567 AC: 189 AN: 33312

American (AMR) AF: 0.0200 AC: 889 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 381 AN: 26024

East Asian (EAS) AF: 0.000935 AC: 37 AN: 39592

South Asian (SAS) AF: 0.0155 AC: 1337 AN: 86004

European-Finnish (FIN) AF: 0.0232 AC: 1236 AN: 53176

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5756

European-Non Finnish (NFE) AF: 0.0458 AC: 50581 AN: 1104874

Other (OTH) AF: 0.0313 AC: 1881 AN: 60078

GnomAD4 genome AF: 0.0282 AC: 4283 AN: 151920 Hom.: 71 Cov.: 30 AF XY: 0.0270 AC XY: 2008 AN XY: 74242

African (AFR) AF: 0.00784 AC: 325 AN: 41446

American (AMR) AF: 0.0314 AC: 480 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3464

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5154

South Asian (SAS) AF: 0.0169 AC: 81 AN: 4794

European-Finnish (FIN) AF: 0.0224 AC: 237 AN: 10574

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0441 AC: 2995 AN: 67914

Other (OTH) AF: 0.0194 AC: 41 AN: 2108

Alfa AF: 0.00869 Hom.: 2

Bravo AF: 0.0277

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs527665020; hg19: chr15-57212228;