rs763289805

Positions:

• chr14-75971215-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000238682.8(TGFB3):​c.557T>G​(p.Ile186Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I186I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFB3 ENST00000238682.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 8.69

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]

TGFB3-AS1 (HGNC:53144): (TGFB3 antisense RNA 1)

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.557T>G	p.Ile186Ser	missense_variant	3/7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.557T>G	p.Ile186Ser	missense_variant	4/8		NP_001316868.1
TGFB3	NM_001329938.2	c.557T>G	p.Ile186Ser	missense_variant	3/5		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.557T>G	p.Ile186Ser	missense_variant	3/7	1	NM_003239.5	ENSP00000238682	P1
TGFB3-AS1	ENST00000553732.1	n.292A>C		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2024	Has been reported in a patient with a hereditary connective tissue disorder (PMID: 35918752); 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: 35903967, 35918752) -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 17, 2018	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The p.I186S variant (also known as c.557T>G), located in coding exon 3 of the TGFB3 gene, results from a T to G substitution at nucleotide position 557. The isoleucine at codon 186 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in connective tissue disorder cohorts (Veatch OJ et al. BMC Med Genomics, 2022 Aug;15:169; Steinle J et al. Am J Med Genet A, 2022 Oct;188:3016-3023). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

TGFB3-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2024

The TGFB3 c.557T>G variant is predicted to result in the amino acid substitution p.Ile186Ser. This variant was reported as a variant of uncertain significance in an individual with connective tissue disorder (Veatch et al 2022. PubMed ID: 35918752). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Rienhoff syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 410272). This variant has not been reported in the literature in individuals affected with TGFB3-related conditions. This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 186 of the TGFB3 protein (p.Ile186Ser). This variant is present in population databases (rs763289805, gnomAD 0.0009%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.60	P;.
Vest4		0.69
MVP		0.69
MPC		1.6
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.68
gMVP		0.86

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: rs763289805; hg19: chr14-76437558;