1-218437437-GCC-ACA

Variant names:

• chr1-218437437-GCC-ACA
• NM_003238.6:c.1027_1029delGCCinsACA
• TGFB2 p.Ala343Thr

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_003238.6(TGFB2):​c.1027_1029delGCCinsACA​(p.Ala343Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A343A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TGFB2 NM_003238.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 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):

• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003238.6
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1027_1029delGCCinsACA	p.Ala343Thr	missense	N/A	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.1111_1113delGCCinsACA	p.Ala371Thr	missense	N/A	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.2278_2280delGCCinsACA		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.1027_1029delGCCinsACA	p.Ala343Thr	missense	N/A	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.1111_1113delGCCinsACA	p.Ala371Thr	missense	N/A	ENSP00000355896.4	P61812-2
	TGFB2	ENST00000479322.1	TSL:3	n.511_513delGCCinsACA		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

hg19: chr1-218610779;