rs587777617

Variant names:

• chr14-75963343-C-T
• rs587777617
• NM_003239.5:c.899G>A

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.899G>A​(p.Arg300Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,854 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R300W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFB3 NM_003239.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.13
• Publications: 8 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 chr14-75963344-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 203490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 14-75963343-C-T is Pathogenic according to our data. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75963343-C-T is described in CliVar as Pathogenic. Clinvar id is 143945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.899G>A	p.Arg300Gln	missense_variant	Exon 5 of 7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.899G>A	p.Arg300Gln	missense_variant	Exon 6 of 8		NP_001316868.1
TGFB3	NM_001329938.2	c.899G>A	p.Arg300Gln	missense_variant	Exon 5 of 5		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.899G>A	p.Arg300Gln	missense_variant	Exon 5 of 7	1	NM_003239.5	ENSP00000238682.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000439 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 12, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with Loeys-Dietz syndrome referred for genetic testing at GeneDx and in patients with suspected heritable thoracic aortic disorders or a clinical diagnosis of Loeys-Dietz syndrome in published literature (PMID: 29907982, 24798638, 28425089, 31898322, 35668506); Not observed at significant frequency 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: 24798638, 25835445, 31898322, 26247899, 26184463, 28425089, 29392890, 35668506, 36529632, 37010288, 29907982) -

Rienhoff syndrome Pathogenic:2

Jul 03, 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 glutamine, which is neutral and polar, at codon 300 of the TGFB3 protein (p.Arg300Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Loeys-Dietz syndrome or Rienhoff syndrome (PMID: 24798638, 28425089). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143945). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TGFB3 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg300 amino acid residue in TGFB3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24798638, 25835445, 26184463, 28425089). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		6.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.61		Loss of MoRF binding (P = 0.0281);Loss of MoRF binding (P = 0.0281);
MVP		0.88
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.66
gMVP		0.90
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777617; hg19: chr14-76429686;