TGFB3 p.Asn118Lys

Variant names:

• chr14-75971717-G-T
• NM_003239.5:c.354C>A
• TGFB3 p.Asn118Lys

Your query was ambiguous. Multiple possible variants found:

• chr14-75971717-G-T
• chr14-75971717-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003239.5(TGFB3):​c.354C>A​(p.Asn118Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N118N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFB3 NM_003239.5 missense, splice_region
• Scores: Splicing: ADA: 0.00009364
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.299
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

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.354C>A	p.Asn118Lys	missense splice_region	Exon 2 of 7	NP_003230.1	A5YM40
	TGFB3	NM_001329939.2		c.354C>A	p.Asn118Lys	missense splice_region	Exon 3 of 8	NP_001316868.1	A5YM40
	TGFB3	NM_001329938.2		c.354C>A	p.Asn118Lys	missense splice_region	Exon 2 of 5	NP_001316867.1	P10600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.354C>A	p.Asn118Lys	missense splice_region	Exon 2 of 7	ENSP00000238682.3	P10600-1
	TGFB3	ENST00000556285.1	TSL:1	c.354C>A	p.Asn118Lys	missense splice_region	Exon 2 of 5	ENSP00000451110.1	P10600-2
	TGFB3	ENST00000964917.1		c.516C>A	p.Asp172Glu	missense splice_region	Exon 3 of 8	ENSP00000634976.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.30
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.40
Sift	Benign	0.13	T
Sift4G	Benign	0.19	T
Varity_R		0.073
gMVP		0.62
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.87		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-76438060;