15-67066155-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>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000139 in 1,439,974 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: 0.0000014 (0 hom.)
• Consequence: SMAD3 NM_005902.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 [Likely_pathogenic] in ClinVar as 1174530
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-67066155-A-T is Pathogenic according to our data. Variant chr15-67066155-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 930360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67066155-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.1A>T	p.Met1?	start_lost	1/9	ENST00000327367.9
SMAD3	NM_001407011.1	c.1A>T	p.Met1?	start_lost	1/10
SMAD3	NM_001407012.1	c.1A>T	p.Met1?	start_lost	1/8
SMAD3	NM_001407013.1	c.1A>T	p.Met1?	start_lost	1/8

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439974 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 714350

Gnomad4 AFR exome AF: 0.00

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aneurysm-osteoarthritis syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_005902.4:c.1A>T (chr15:67066155) in SMAD3 was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PVS1, PP5) this variant classifies as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 24, 2021

This variant has been observed in individuals affected with thoracic aortic aneurysm and/or dissection or arterial dissection (PMID: 29907982, 33125268 , Invitae). For these reasons, this allele has been classified as Pathogenic. This variant disrupts the initiator methionine in SMAD3. If translation initiates from the next in-frame methionine, the SMAD3 protein would no longer include the region containing the p.Arg93 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (PMID: 29543232, Invitae), which suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change affects the initiator methionine of the SMAD3 mRNA. The next in-frame methionine is located at codon 106. -

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	0.94
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.55	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; COSMIC: COSV105234210; COSMIC: COSV105234210;