14-75971128-C-G

Position:

• chr14-75971128-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_003239.5(TGFB3):​c.644G>C​(p.Arg215Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TGFB3 NM_003239.5 missense, splice_region
• Scores: Splicing: ADA: 0.9248
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.644G>C	p.Arg215Thr	missense_variant, splice_region_variant	3/7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.644G>C	p.Arg215Thr	missense_variant, splice_region_variant	4/8		NP_001316868.1
TGFB3	NM_001329938.2	c.644G>C	p.Arg215Thr	missense_variant, splice_region_variant	3/5		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.644G>C	p.Arg215Thr	missense_variant, splice_region_variant	3/7	1	NM_003239.5	ENSP00000238682	P1
TGFB3-AS1	ENST00000553732.1	n.205C>G		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Oct 02, 2022

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 215 of the TGFB3 protein (p.Arg215Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TGFB3-related conditions. 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. 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	0.27
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.19
Sift	Benign	0.19	T;D
Sift4G	Benign	0.52	T;T
Polyphen		0.66	P;.
Vest4		0.77
MutPred		0.35		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.78
MPC		1.3
ClinPred		0.80	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.57
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-76437471;