chr1-218379955-A-G

Variant names:

• chr1-218379955-A-G
• rs3892225
• NM_003238.6:c.347-25214A>G

Variant summary

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

The NM_003238.6(TGFB2):​c.347-25214A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 152,140 control chromosomes in the GnomAD database, including 2,226 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 0.17 (2226 hom., cov: 32)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• 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, 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=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 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.347-25214A>G		intron	N/A	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.430+16538A>G		intron	N/A	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.1713-25214A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.347-25214A>G		intron	N/A	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.430+16538A>G		intron	N/A	ENSP00000355896.4	P61812-2
	TGFB2	ENST00000488793.1	TSL:3	n.11-25214A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25839 AN: 152022 Hom.: 2224 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.170 AC: 25875 AN: 152140 Hom.: 2226 Cov.: 32 AF XY: 0.172 AC XY: 12788 AN XY: 74398

African (AFR) AF: 0.151 AC: 6246 AN: 41494

American (AMR) AF: 0.167 AC: 2553 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 605 AN: 3472

East Asian (EAS) AF: 0.178 AC: 920 AN: 5176

South Asian (SAS) AF: 0.212 AC: 1023 AN: 4818

European-Finnish (FIN) AF: 0.186 AC: 1971 AN: 10584

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11920 AN: 67992

Other (OTH) AF: 0.199 AC: 420 AN: 2106

Alfa AF: 0.177 Hom.: 8050

Bravo AF: 0.170

Asia WGS AF: 0.164 AC: 570 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.6
DANN	Benign	0.64
PhyloP100		0.049
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: rs3892225;

hg19: chr1-218553297;