14-75963344-G-A

Variant names:

• chr14-75963344-G-A
• rs796051885
• NM_003239.5:c.898C>T

Variant summary

Our verdict is Pathogenic. The variant received 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:9
• Conservation: PhyloP100: 2.54
• Publications: 6 publications found

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]

IFT43 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• short-rib thoracic dysplasia 18 with polydactyly

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• retinitis pigmentosa 81

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 203490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003239.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	NM_003239.5	MANE Select	c.898C>T	p.Arg300Trp	missense	Exon 5 of 7	NP_003230.1
	TGFB3	NM_001329939.2		c.898C>T	p.Arg300Trp	missense	Exon 6 of 8	NP_001316868.1
	TGFB3	NM_001329938.2		c.898C>T	p.Arg300Trp	missense	Exon 5 of 5	NP_001316867.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.898C>T	p.Arg300Trp	missense	Exon 5 of 7	ENSP00000238682.3
	TGFB3	ENST00000556285.1	TSL:1	c.898C>T	p.Arg300Trp	missense	Exon 5 of 5	ENSP00000451110.1
	TGFB3	ENST00000556674.2	TSL:3	c.898C>T	p.Arg300Trp	missense	Exon 6 of 8	ENSP00000502685.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000429 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rienhoff syndrome Pathogenic:4

Oct 18, 2024

Clinical Genetics Laboratory, Region Ostergotland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria were applied in classifying this variant: PS4, PM2, PM5_supp, PM6, PP3_strong, PP1_Strong

Apr 07, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence 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 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.

Aug 14, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.87 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000203490 /PMID: 25835445). Different missense changes at the same codon (p.Arg300Gln, p.Arg300Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143945 /PMID: 24798638, 26184463). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Pathogenic:3

Nov 10, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 13, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 05, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25835445, 27848944, 29392890, 31898322)

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Nov 13, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 04, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.66		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
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs796051885; hg19: chr14-76429687; COSMIC: COSV53170944; COSMIC: COSV53170944;