rs532403511

Positions:

• chr14-75971643-C-A
• chr14-75971643-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003239.5(TGFB3):​c.428G>T​(p.Arg143Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFB3 NM_003239.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15827668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.428G>T	p.Arg143Ile	missense_variant	2/7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.428G>T	p.Arg143Ile	missense_variant	3/8		NP_001316868.1
TGFB3	NM_001329938.2	c.428G>T	p.Arg143Ile	missense_variant	2/5		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.428G>T	p.Arg143Ile	missense_variant	2/7	1	NM_003239.5	ENSP00000238682	P1
TGFB3	ENST00000556285.1	c.428G>T	p.Arg143Ile	missense_variant	2/5	1		ENSP00000451110
TGFB3	ENST00000556674.2	c.428G>T	p.Arg143Ile	missense_variant	3/8	3		ENSP00000502685	P1
IFT43	ENST00000555677.5	n.90-17242C>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rienhoff syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 12, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TGFB3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with isoleucine at codon 143 of the TGFB3 protein (p.Arg143Ile). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-1.6	N;N
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.8	N;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0030	B;.
Vest4		0.37
MutPred		0.54		Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);
MVP		0.47
MPC		1.1
ClinPred		0.53	D
GERP RS		4.8
Varity_R		0.095
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs532403511; hg19: chr14-76437986;