1-218406643-A-G

Variant names:

• chr1-218406643-A-G
• rs1891467
• NM_003238.6:c.510+1311A>G

Variant summary

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

The NM_001135599.4(TGFB2):​c.594+1311A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 151,942 control chromosomes in the GnomAD database, including 10,510 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 0.34 (10510 hom., cov: 32)
• Consequence: TGFB2 NM_001135599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459
• Publications: 17 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135599.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	NM_003238.6	MANE Select	c.510+1311A>G		intron	N/A	NP_003229.1
	TGFB2	NM_001135599.4		c.594+1311A>G		intron	N/A	NP_001129071.1
	TGFB2	NR_138148.2		n.1876+1311A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.510+1311A>G		intron	N/A	ENSP00000355897.4
	TGFB2	ENST00000366929.4	TSL:1	c.594+1311A>G		intron	N/A	ENSP00000355896.4
	TGFB2	ENST00000488793.1	TSL:3	n.174+1311A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52119 AN: 151824 Hom.: 10477 Cov.: 32

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.344 AC: 52218 AN: 151942 Hom.: 10510 Cov.: 32 AF XY: 0.351 AC XY: 26041 AN XY: 74232

African (AFR) AF: 0.494 AC: 20460 AN: 41392

American (AMR) AF: 0.444 AC: 6783 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1072 AN: 3468

East Asian (EAS) AF: 0.667 AC: 3448 AN: 5168

South Asian (SAS) AF: 0.379 AC: 1826 AN: 4818

European-Finnish (FIN) AF: 0.276 AC: 2908 AN: 10540

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14723 AN: 67966

Other (OTH) AF: 0.355 AC: 748 AN: 2110

Alfa AF: 0.265 Hom.: 11714

Bravo AF: 0.366

Asia WGS AF: 0.482 AC: 1677 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		-0.46
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: rs1891467; hg19: chr1-218579985; COSMIC: COSV65108720;