chr1-218391539-C-T

Variant names:

• chr1-218391539-C-T
• rs947712
• NM_003238.6:c.347-13630C>T

Variant summary

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

The NM_003238.6(TGFB2):​c.347-13630C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 152,016 control chromosomes in the GnomAD database, including 13,214 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 0.41 (13214 hom., cov: 33)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.411
• Publications: 14 publications found

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

TGFB2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.347-13630C>T		intron_variant	Intron 1 of 6	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.431-13630C>T		intron_variant	Intron 2 of 7		NP_001129071.1
TGFB2	NR_138148.2	n.1713-13630C>T		intron_variant	Intron 1 of 6
TGFB2	NR_138149.2	n.1797-13630C>T		intron_variant	Intron 2 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.347-13630C>T		intron_variant	Intron 1 of 6	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.431-13630C>T		intron_variant	Intron 2 of 7	1		ENSP00000355896.4
TGFB2	ENST00000488793.1	n.11-13630C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62458 AN: 151900 Hom.: 13202 Cov.: 33

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.407

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

GnomAD4 genome AF: 0.411 AC: 62499 AN: 152016 Hom.: 13214 Cov.: 33 AF XY: 0.415 AC XY: 30810 AN XY: 74274

African (AFR) AF: 0.484 AC: 20082 AN: 41464

American (AMR) AF: 0.464 AC: 7093 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1291 AN: 3470

East Asian (EAS) AF: 0.538 AC: 2777 AN: 5158

South Asian (SAS) AF: 0.516 AC: 2483 AN: 4816

European-Finnish (FIN) AF: 0.378 AC: 3981 AN: 10542

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23466 AN: 67968

Other (OTH) AF: 0.407 AC: 858 AN: 2108

Alfa AF: 0.369 Hom.: 19948

Bravo AF: 0.421

Asia WGS AF: 0.507 AC: 1762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.43
DANN	Benign	0.51
PhyloP100		-0.41
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: rs947712; hg19: chr1-218564881;