rs796051885

Positions:

• chr14-75963344-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003239.5(TGFB3):​c.898C>T​(p.Arg300Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R300Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TGFB3 NM_003239.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.54

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-75963343-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 14-75963344-G-A is Pathogenic according to our data. Variant chr14-75963344-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963344-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB3	NM_003239.5	c.898C>T	p.Arg300Trp	missense_variant	5/7	ENST00000238682.8
TGFB3	NM_001329939.2	c.898C>T	p.Arg300Trp	missense_variant	6/8
TGFB3	NM_001329938.2	c.898C>T	p.Arg300Trp	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB3	ENST00000238682.8	c.898C>T	p.Arg300Trp	missense_variant	5/7	1	NM_003239.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2022	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25835445, 31898322, 27848944, 29392890) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 13, 2018	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2018	The p.R300W pathogenic mutation (also known as c.898C>T), located in coding exon 5 of the TGFB3 gene, results from a C to T substitution at nucleotide position 898. The arginine at codon 300 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is located in the latency-associated peptide domain and has been reported in individuals and families with hypertelorism, bifid uvula and/or cleft palate, and other overlapping Loeys-Dietz and Marfan syndrome-like features (Bertoli-Avella AM et al. J. Am. Coll. Cardiol., 2015 Apr;65:1324-36; Trujillano D et al. Eur. J. Hum. Genet., 2017 02;25:176-182; Schepers D et al. Hum. Mutat., 2018 May;39:621-634). Other substitutions at this amino acid position, p.R300Q and p.R300G, have been identified in families with similar clinical findings, as well as in an affected individual reported as a de novo case (Matyas G et al. Am. J. Med. Genet. A, 2014 Aug;164A:2141-3; Kuechler A et al. Mol. Cell. Probes, 2015 Oct;29:330-4). Internal structural analysis indicates that alterations at this position disrupt the putative furin pro-peptide cleavage motif of the protein (Dubois CM et al. J. Biol. Chem., 1995 May;270:10618-24; Lafyatis R. Nat Rev Rheumatol, 2014 Dec;10:706-19; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Rienhoff syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 17, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 300 of the TGFB3 protein (p.Arg300Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 25835445, 31898322). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 203490). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGFB3 protein function. This variant disrupts the p.Arg300 amino acid residue in TGFB3. Other variant(s) that disrupt this residue have been observed in individuals with TGFB3-related conditions (PMID: 24798638, 26184463), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.66		Loss of disorder (P = 0.0104);Loss of disorder (P = 0.0104);
MVP		0.89
MPC		1.6
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.75
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs796051885; hg19: chr14-76429687; COSMIC: COSV53170944; COSMIC: COSV53170944;