NM_003238.6:c.347-3309G>A

Variant names:

• chr1-218401860-G-A
• rs1317681
• NM_003238.6:c.347-3309G>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.347-3309G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 152,108 control chromosomes in the GnomAD database, including 3,393 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 0.19 (3393 hom., cov: 32)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.505
• Publications: 13 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.347-3309G>A		intron_variant	Intron 1 of 6	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.431-3309G>A		intron_variant	Intron 2 of 7		NP_001129071.1
TGFB2	NR_138148.2	n.1713-3309G>A		intron_variant	Intron 1 of 6
TGFB2	NR_138149.2	n.1797-3309G>A		intron_variant	Intron 2 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.347-3309G>A		intron_variant	Intron 1 of 6	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.431-3309G>A		intron_variant	Intron 2 of 7	1		ENSP00000355896.4
TGFB2	ENST00000488793.1	n.11-3309G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29294 AN: 151990 Hom.: 3393 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.193 AC: 29306 AN: 152108 Hom.: 3393 Cov.: 32 AF XY: 0.199 AC XY: 14798 AN XY: 74344

African (AFR) AF: 0.152 AC: 6318 AN: 41522

American (AMR) AF: 0.316 AC: 4831 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 699 AN: 3470

East Asian (EAS) AF: 0.503 AC: 2585 AN: 5138

South Asian (SAS) AF: 0.296 AC: 1425 AN: 4812

European-Finnish (FIN) AF: 0.180 AC: 1904 AN: 10580

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10922 AN: 67986

Other (OTH) AF: 0.205 AC: 434 AN: 2112

Alfa AF: 0.177 Hom.: 8252

Bravo AF: 0.205

Asia WGS AF: 0.342 AC: 1189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.51
DANN	Benign	0.80
PhyloP100		-0.51
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: rs1317681; hg19: chr1-218575202; COSMIC: COSV65108713;