chr1-218386133-C-A

Variant names:

• chr1-218386133-C-A
• rs12029576
• NM_003238.6:c.347-19036C>A

Variant summary

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

The NM_003238.6(TGFB2):​c.347-19036C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 152,026 control chromosomes in the GnomAD database, including 26,138 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 0.55 (26138 hom., cov: 32)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.722
• Publications: 10 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.347-19036C>A		intron_variant	Intron 1 of 6	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.431-19036C>A		intron_variant	Intron 2 of 7		NP_001129071.1
TGFB2	NR_138148.2	n.1713-19036C>A		intron_variant	Intron 1 of 6
TGFB2	NR_138149.2	n.1797-19036C>A		intron_variant	Intron 2 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.347-19036C>A		intron_variant	Intron 1 of 6	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.431-19036C>A		intron_variant	Intron 2 of 7	1		ENSP00000355896.4
TGFB2	ENST00000488793.1	n.11-19036C>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82863 AN: 151908 Hom.: 26138 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.576

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

GnomAD4 genome AF: 0.545 AC: 82884 AN: 152026 Hom.: 26138 Cov.: 32 AF XY: 0.548 AC XY: 40733 AN XY: 74296

African (AFR) AF: 0.209 AC: 8692 AN: 41492

American (AMR) AF: 0.636 AC: 9713 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2264 AN: 3468

East Asian (EAS) AF: 0.494 AC: 2531 AN: 5126

South Asian (SAS) AF: 0.552 AC: 2655 AN: 4814

European-Finnish (FIN) AF: 0.702 AC: 7417 AN: 10566

Middle Eastern (MID) AF: 0.590 AC: 171 AN: 290

European-Non Finnish (NFE) AF: 0.699 AC: 47520 AN: 67968

Other (OTH) AF: 0.576 AC: 1216 AN: 2110

Alfa AF: 0.653 Hom.: 18350

Bravo AF: 0.524

Asia WGS AF: 0.532 AC: 1849 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.3
DANN	Benign	0.79
PhyloP100		-0.72
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: rs12029576; hg19: chr1-218559475;