1-218423702-G-A

Variant names:

• chr1-218423702-G-A
• rs6671370
• NM_003238.6:c.511-10380G>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.511-10380G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 151,864 control chromosomes in the GnomAD database, including 12,590 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 0.39 (12590 hom., cov: 32)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.626
• Publications: 4 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 4

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003238.6. 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
	TGFB2	NM_003238.6	MANE Select	c.511-10380G>A		intron	N/A	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.595-10380G>A		intron	N/A	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.1877-10380G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.511-10380G>A		intron	N/A	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.595-10380G>A		intron	N/A	ENSP00000355896.4	P61812-2
	TGFB2	ENST00000488793.1	TSL:3	n.175-10380G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58902 AN: 151746 Hom.: 12560 Cov.: 32

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.378

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

GnomAD4 genome AF: 0.388 AC: 58984 AN: 151864 Hom.: 12590 Cov.: 32 AF XY: 0.393 AC XY: 29182 AN XY: 74228

African (AFR) AF: 0.510 AC: 21118 AN: 41396

American (AMR) AF: 0.480 AC: 7311 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1129 AN: 3468

East Asian (EAS) AF: 0.713 AC: 3672 AN: 5148

South Asian (SAS) AF: 0.368 AC: 1771 AN: 4814

European-Finnish (FIN) AF: 0.319 AC: 3362 AN: 10554

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19392 AN: 67940

Other (OTH) AF: 0.381 AC: 803 AN: 2106

Alfa AF: 0.339 Hom.: 1180

Bravo AF: 0.410

Asia WGS AF: 0.484 AC: 1685 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.44
DANN	Benign	0.49
PhyloP100		-0.63
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6671370;

hg19: chr1-218597044;