rs1555360047

Positions:

• chr14-75959320-TTCAG-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000238682.8(TGFB3):​c.1102_1105del​(p.Leu368ThrfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFB3 ENST00000238682.8 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

Genes affected

TGFB3 (HGNC:11769): (transforming growth factor beta 3) 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. This protein is involved in embryogenesis and cell differentiation, and may play a role in wound healing. Mutations in this gene are a cause of aortic aneurysms and dissections, as well as familial arrhythmogenic right ventricular dysplasia 1. [provided by RefSeq, Aug 2016]

IFT43 (HGNC:29669): (intraflagellar transport 43) This gene encodes a subunit of the intraflagellar transport complex A (IFT-A). IFT-A is a multiprotein complex that plays an important role in cilia assembly and maintenance by mediating retrograde ciliary transport. Mutations in this gene are a cause of cranioectodermal dysplasia-3 (CED3), also known as Sensenbrenner syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-75959320-TTCAG-T is Pathogenic according to our data. Variant chr14-75959320-TTCAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.1102_1105del	p.Leu368ThrfsTer18	frameshift_variant	7/7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.1102_1105del	p.Leu368ThrfsTer18	frameshift_variant	8/8		NP_001316868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.1102_1105del	p.Leu368ThrfsTer18	frameshift_variant	7/7	1	NM_003239.5	ENSP00000238682	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2020

The c.1102_1105delCTGA variant, located in coding exon 7 of the TGFB3 gene, results from a deletion of 4 nucleotides at nucleotide positions 1102 to 1105, causing a translational frameshift with a predicted alternate stop codon (p.L368Tfs*8). This frameshift occurs at the 3' terminus of TGFB3, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 44 amino acids of the protein. However, frameshifts are typically deleterious in nature, and internal structural analysis indicates that this alteration eliminates most of the homodimer interface-forming residues and “cysteine knot” motif, both of which are critical for proper protein function (Mittl PR et al. Protein Sci. 1996;5(7):1261-71). In addition, two other truncations near the 3' terminus, p.Y365* and c.1157delT (p.L386Rfs*21), have been reported in patients with clinical features of Marfan syndrome (MFS) and/or Loeys-Dietz syndrome (LDS) (Bertoli-Avella AM et al. J Am Coll Cardiol. 2015;65:1324-36). Based on the majority of available evidence to date, this alteration is likely to be pathogenic. -

Arrhythmogenic right ventricular dysplasia 1;C3810012:Rienhoff syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 26, 2021

- -

Rienhoff syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 05, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TGFB3 protein in which other variant(s) (p.Lys407*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 520206). This variant has not been reported in the literature in individuals affected with TGFB3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu368Thrfs*18) in the TGFB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the TGFB3 protein. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555360047; hg19: chr14-76425663;