rs1555413579

chr15-67181383-GC-TT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP2 PP5_Moderate

The NM_005902.4(SMAD3):c.801_802delinsTT(p.Glu267_Arg268delinsAspCys) variant causes a missense change. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E267E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.95

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005902.4
• PP2: Missense variant where missense usually causes diseases, SMAD3
• PP5: Variant 15-67181383-GC-TT is Pathogenic according to our data. Variant chr15-67181383-GC-TT is described in ClinVar as [Pathogenic]. Clinvar id is 477580.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.801_802delinsTT	p.Glu267_Arg268delinsAspCys	missense_variant	6/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.801_802delinsTT	p.Glu267_Arg268delinsAspCys	missense_variant	6/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with SMAD3-related conditions. ClinVar contains an entry for this variant (Variation ID: 477580). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the SMAD3 protein in which other variant(s) (p.Arg268His) have been determined to be pathogenic (PMID: 25944730, 26854089; 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. This variant, c.801_802delinsTT, is a complex sequence change that results in the deletion of 2 and insertion of 2 amino acid(s) in the SMAD3 protein (p.Glu267_Arg268delinsAspCys). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555413579; hg19: chr15-67473721;