NM_003239.5:c.1221G>C

Variant names:

• chr14-75959205-C-G
• rs769218542
• NM_003239.5:c.1221G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_003239.5(TGFB3):​c.1221G>C​(p.Lys407Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K407E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFB3 NM_003239.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.35
• Publications: 0 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003239.5
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003239.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	NM_003239.5	MANE Select	c.1221G>C	p.Lys407Asn	missense	Exon 7 of 7	NP_003230.1	A5YM40
	TGFB3	NM_001329939.2		c.1221G>C	p.Lys407Asn	missense	Exon 8 of 8	NP_001316868.1	A5YM40

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.1221G>C	p.Lys407Asn	missense	Exon 7 of 7	ENSP00000238682.3	P10600-1
	TGFB3	ENST00000964917.1		c.1383G>C	p.Lys461Asn	missense	Exon 8 of 8	ENSP00000634976.1
	TGFB3	ENST00000556674.2	TSL:3	c.1221G>C	p.Lys407Asn	missense	Exon 8 of 8	ENSP00000502685.1	P10600-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	Rienhoff syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.56		Loss of methylation at K407 (P = 0.0122)
MVP		0.79
MPC		1.7
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.91
gMVP		0.75
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs769218542; hg19: chr14-76425548;