rs863223761

Variant names:

• chr15-67181455-T-C
• rs863223761
• NM_005902.4:c.871+2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_005902.4(SMAD3):​c.871+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.16666667 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-67181455-T-C is Pathogenic according to our data. Variant chr15-67181455-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213795.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.871+2T>C		splice_donor_variant, intron_variant	Intron 6 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.871+2T>C		splice_donor_variant, intron_variant	Intron 6 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:1

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 6 of the SMAD3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with SMAD3-related conditions (PMID: 32597575). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213795). Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 32597575). For these reasons, this variant has been classified as Pathogenic. -

Oct 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.871+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 6 in the SMAD3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Loeys-Dietz syndrome Pathogenic:1

Aug 24, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.871+2T>C variant in SMAD3 has not been reported in the literature and was absent from large population studies. This variant is reported in ClinVar (allele ID: 210285). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the SMAD3 gene is an established disease mechanism in autosomal dominant Loeys-Dietz syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Loeys-Dietz syndrome. ACMG/AMP Criteria applied: PVS1; PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	0.98
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.91	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 5
DS_DL_spliceai		0.93		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: rs863223761; hg19: chr15-67473793;