GeneBe

rs745672741

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_005902.4(SMAD3):​c.401-6G>A variant causes a splice region, 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
NM_005902.4 splice_region, intron

Scores

2
Splicing: ADA: 0.9984
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.91

Publications

3 publications found
Variant links:
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]
SMAD3 Gene-Disease associations (from GenCC):
  • aneurysm-osteoarthritis syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
  • familial thoracic aortic aneurysm and aortic dissection
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 15-67165247-G-A is Pathogenic according to our data. Variant chr15-67165247-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 213782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMAD3NM_005902.4 linkc.401-6G>A splice_region_variant, intron_variant Intron 2 of 8 ENST00000327367.9 NP_005893.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMAD3ENST00000327367.9 linkc.401-6G>A splice_region_variant, intron_variant Intron 2 of 8 1 NM_005902.4 ENSP00000332973.4

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
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SMAD3: PVS1, PM2, PS4:Moderate -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Apr 18, 2025
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 was reported in individual(s) with features consistent with SMAD3-related Loeys-Dietz syndrome (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; Dekker S et al. Eur J Med Genet. 2022 Feb;65(2):104424; Ambry internal data). RNA analysis confirmed the use of a cryptic acceptor site, leading to an out of frame consequence (Arnaud P et al. Genet Med, 2019 09;21:2015-2024). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Aneurysm-osteoarthritis syndrome Pathogenic:2
May 13, 2023
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 04, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Connective tissue disorder Pathogenic:1
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.60
CADD
Uncertain
25
DANN
Benign
0.80
PhyloP100
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=17/83
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs745672741; hg19: chr15-67457585; API