14-75971682-T-C

Position:

• chr14-75971682-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003239.5(TGFB3):​c.389A>G​(p.Lys130Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TGFB3 NM_003239.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.94

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17112562).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.389A>G	p.Lys130Arg	missense_variant	2/7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.389A>G	p.Lys130Arg	missense_variant	3/8		NP_001316868.1
TGFB3	NM_001329938.2	c.389A>G	p.Lys130Arg	missense_variant	2/5		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.389A>G	p.Lys130Arg	missense_variant	2/7	1	NM_003239.5	ENSP00000238682	P1
TGFB3	ENST00000556285.1	c.389A>G	p.Lys130Arg	missense_variant	2/5	1		ENSP00000451110
TGFB3	ENST00000556674.2	c.389A>G	p.Lys130Arg	missense_variant	3/8	3		ENSP00000502685	P1
IFT43	ENST00000555677.5	n.90-17203T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251444 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135898

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2021

The p.K130R variant (also known as c.389A>G), located in coding exon 2 of the TGFB3 gene, results from an A to G substitution at nucleotide position 389. The lysine at codon 130 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in cleft lip and palate and thoracic aortic aneurysm and dissection cohorts (Lidral AC et al. Am J Hum Genet, 1998 Aug;63:557-68; Overwater E et al. Hum Mutat, 2018 09;39:1173-1192). This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2022

Reported as mosaic in a 68 year old male with aneurysms of the abdominal aorta and common iliac artery (Overwater et al., 2018); Also reported in an individual with submucous cleft palate whose mother and maternal relatives presented with scarring of the lip (Lidral et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16327884, 22978696, 9683588, 29907982) -

Rienhoff syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 05, 2021

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 130 of the TGFB3 protein (p.Lys130Arg). This variant is present in population databases (rs780051351, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of TGFB3-related conditions (PMID: 9683588, 29907982). This variant is also known as 383A>G, Lys128Arg. ClinVar contains an entry for this variant (Variation ID: 477637). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.63	N;N
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.13
Sift	Benign	0.97	T;T
Sift4G	Benign	0.79	T;T
Polyphen		0.0	B;.
Vest4		0.26
MutPred		0.47		Loss of methylation at K130 (P = 0.0043);Loss of methylation at K130 (P = 0.0043);
MVP		0.63
MPC		0.50
ClinPred		0.17	T
GERP RS		5.7
Varity_R		0.093
gMVP		0.55

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: rs780051351; hg19: chr14-76438025;