NM_005902.4:c.1269T>A

Variant names:

• chr15-67190527-T-A
• rs1060500772
• NM_005902.4:c.1269T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_005902.4(SMAD3):​c.1269T>A​(p.Ser423Arg) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S423N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.755
• Publications: 4 publications found

Genes affected

SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

SMAD3 Gene-Disease associations (from GenCC):

• aneurysm-osteoarthritis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005902.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-67190526-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 449264.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.1269T>A	p.Ser423Arg	missense	Exon 9 of 9	NP_005893.1
	SMAD3	NM_001407011.1		c.1380T>A	p.Ser460Arg	missense	Exon 10 of 10	NP_001393940.1
	SMAD3	NM_001145103.2		c.1137T>A	p.Ser379Arg	missense	Exon 9 of 9	NP_001138575.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.1269T>A	p.Ser423Arg	missense	Exon 9 of 9	ENSP00000332973.4
	SMAD3	ENST00000439724.7	TSL:1	c.1137T>A	p.Ser379Arg	missense	Exon 9 of 9	ENSP00000401133.3
	SMAD3	ENST00000540846.6	TSL:1	c.954T>A	p.Ser318Arg	missense	Exon 9 of 9	ENSP00000437757.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Dec 25, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with arginine at codon 423 of the SMAD3 protein (p.Ser423Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMAD3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		-0.76
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.78
MutPred		0.41		Gain of MoRF binding (P = 0.0026)
MVP		0.97
MPC		2.5
ClinPred		1.0	D
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.99
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1060500772; hg19: chr15-67482865;