NM_005902.4:c.309A>C

Variant names:

• chr15-67164997-A-C
• rs1065080
• NM_005902.4:c.309A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_005902.4(SMAD3):​c.309A>C​(p.Leu103Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L103L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SMAD3 NM_005902.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 0 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28622442).
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.309A>C	p.Leu103Leu	synonymous	Exon 2 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.309A>C	p.Leu103Leu	synonymous	Exon 2 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.177A>C	p.Leu59Leu	synonymous	Exon 2 of 9	NP_001138575.1	P84022-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.309A>C	p.Leu103Leu	synonymous	Exon 2 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000439724.7	TSL:1	c.177A>C	p.Leu59Leu	synonymous	Exon 2 of 9	ENSP00000401133.3	P84022-2
	SMAD3	ENST00000540846.6	TSL:1	c.-7A>C		5_prime_UTR	Exon 2 of 9	ENSP00000437757.2	P84022-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.0
DANN	Benign	0.84
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.29	T
PhyloP100		1.3
PROVEAN	Pathogenic	-9.0	D
Vest4		0.26
MVP		0.81
GERP RS		2.4
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1065080; hg19: chr15-67457335;