rs1555405092

Positions:

• chr15-67066155-A-C
• chr15-67066155-A-G
• chr15-67066155-A-T

Variant summary

Our verdict is Pathogenic. Variant got 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 start lost 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 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_005902.4 (SMAD3) was described as [Pathogenic] in Lovd
• 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/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1A>C	p.Met1?	start_lost	1/9	ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1	c.1A>C	p.Met1?	start_lost	1/10		NP_001393940.1
SMAD3	NM_001407012.1	c.1A>C	p.Met1?	start_lost	1/8		NP_001393941.1
SMAD3	NM_001407013.1	c.1A>C	p.Met1?	start_lost	1/8		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1A>C	p.Met1?	start_lost	1/9	1	NM_005902.4	ENSP00000332973	P1
SMAD3	ENST00000560424.2	c.1A>C	p.Met1?	start_lost	1/10	3		ENSP00000455540
SMAD3	ENST00000559460.6	c.-110+2211A>C		intron_variant		4		ENSP00000453082

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

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 13, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 03, 2023	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; Invitae). 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; Invitae). 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. -

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555405092; hg19: chr15-67358493;