15-67066155-A-C

Variant names:

• chr15-67066155-A-C
• rs1555405092
• NM_005902.4:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_005902.4(SMAD3):​c.1A>C​(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000208 in 1,439,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMAD3 NM_005902.4 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.97
• 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: 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 45 pathogenic variants. Next in-frame start position is after 106 codons. Genomic position: 67165004. Lost 0.247 part of the original CDS.
• PS1: Another start lost variant in NM_005902.4 (SMAD3) was described as [Likely_pathogenic] in ClinVar as 1174530
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-67066155-A-C is Pathogenic according to our data. Variant chr15-67066155-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 9	ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 10		NP_001393940.1
SMAD3	NM_001407012.1	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 8		NP_001393941.1
SMAD3	NM_001407013.1	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 8		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439970 Hom.: 0 Cov.: 33 AF XY: 0.00000280 AC XY: 2 AN XY: 714348

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000303 AC: 1 AN: 32978

American (AMR) AF: 0.00 AC: 0 AN: 42042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25728

East Asian (EAS) AF: 0.00 AC: 0 AN: 38716

South Asian (SAS) AF: 0.00 AC: 0 AN: 83258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4392

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102300

Other (OTH) AF: 0.00 AC: 0 AN: 59438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.004626), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SMAD3 mRNA. The next in-frame methionine is located at codon 106. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with spontaneous coronary artery dissection and/or thoracic aortic aneurysm and/or dissection (PMID: 29907982, 33125268; internal data). ClinVar contains an entry for this variant (Variation ID: 520186). This variant disrupts a region of the SMAD3 protein in which other variant(s) (p.Arg74Trp) have been determined to be pathogenic (PMID: 29510914, 31096651; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 13, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the SMAD3 gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. An alternate alteration in this codon, c.3G>A, has been reported in a child with hypoplastic left heart syndrome and aortic aneurysm, in his father with osteoarthritis and dilated aortic root, and in the proband's younger brother with no cardiac or osteoarthritis findings at the time of evaluation (Fitzgerald KK et al. Case Rep Genet, 2014 Mar;2014:591516). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this variant is likely to be pathogenic. -

Aneurysm-osteoarthritis syndrome Pathogenic:1

May 12, 2025

Clinical Biomedical Laboratory, Shriners Hospital For Children - Canada

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant leads to a start-loss effect. This variant is absent from the Genome Aggregation Database (v.2.1.1). Heterozygous loss of function variants in SMAD3 are an established cause of Loeys-Dietz syndrome 3 (PMID 22167769), which corresponds to the clinical diagnosis of the proband. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.18	D
PhyloP100		5.0
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.54
Sift	Benign	0.35	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.82
MutPred		0.99		Loss of sheet (P = 0.1907);
MVP		0.98
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.19
gMVP		0.32
Mutation Taster		=8/192	disease causing (ClinVar)

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: rs1555405092; hg19: chr15-67358493;