rs745672741

Positions:

• chr15-67165247-G-A
• chr15-67165247-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000327367.9(SMAD3):​c.401-6G>A variant causes a splice region, splice polypyrimidine tract, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMAD3 ENST00000327367.9 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.91

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-67165247-G-A is Pathogenic according to our data. Variant chr15-67165247-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67165247-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.401-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.401-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005902.4	ENSP00000332973	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461870 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727240

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SMAD3: PVS1, PM2, PS4:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 30, 2022	The c.401-6G>A intronic variant results from a G to A substitution 6 nucleotides upstream from coding exon 3 in the SMAD3 gene. This variant has been reported in an individual with osteoarthritis and thoracic aortic aneurysm, as well as in several thoracic aortic aneurysm and dissection (TAAD) cohorts with limited clinical details (Koppen H et al. Headache, 2015 May;55:711-2; (Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Arnaud P et al. Genet Med, 2019 09;21:2015-2024; Hostetler EM et al. J Med Genet, 2019 04;56:252-260). RNA analysis confirmed the use of a cryptic acceptor site, which would lead to an out of frame sequence (Arnaud P et al. Genet Med, 2019 09;21:2015-2024). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change falls in intron 2 of the SMAD3 gene. It does not directly change the encoded amino acid sequence of the SMAD3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with thoracic aortic aneurysms and dissections (TAAD), and Aneurysms-Osteoarthritis Syndrome (OAS) (PMID: 25644172, 25877775; personal communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213782). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aneurysm-osteoarthritis syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 13, 2023	- -

Connective tissue disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	25
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs745672741; hg19: chr15-67457585;