rs769605183
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_005585.5(SMAD6):βc.79_84delβ(p.Ser27_Gly28del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000553 in 1,485,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. G25G) has been classified as Likely benign.
Frequency
Genomes: π 0.00056 ( 0 hom., cov: 32)
Exomes π: 0.00055 ( 0 hom. )
Consequence
SMAD6
NM_005585.5 inframe_deletion
NM_005585.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.63
Genes affected
SMAD6 (HGNC:6772): (SMAD family member 6) The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000559 (85/152132) while in subpopulation AMR AF= 0.00131 (20/15300). AF 95% confidence interval is 0.000866. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd4 at 85 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.79_84del | p.Ser27_Gly28del | inframe_deletion | 1/4 | ENST00000288840.10 | |
SMAD6 | NR_027654.2 | n.1102_1107del | non_coding_transcript_exon_variant | 1/5 | |||
SMAD6 | XR_931827.3 | n.1102_1107del | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.79_84del | p.Ser27_Gly28del | inframe_deletion | 1/4 | 1 | NM_005585.5 | P1 | |
SMAD6 | ENST00000557916.5 | c.79_84del | p.Ser27_Gly28del | inframe_deletion, NMD_transcript_variant | 1/5 | 1 | |||
SMAD6 | ENST00000612349.1 | n.261_266del | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.000559 AC: 85AN: 152024Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000247 AC: 23AN: 92970Hom.: 0 AF XY: 0.000173 AC XY: 9AN XY: 51878
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GnomAD4 exome AF: 0.000553 AC: 737AN: 1333528Hom.: 0 AF XY: 0.000564 AC XY: 371AN XY: 657798
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 27, 2023 | Variant summary: SMAD6 c.79_84delAGCGGC (p.Ser27_Gly28del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 0.00025 in 92970 control chromosomes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD6 causing Aortic Valve Disease phenotype (3.1e-05), strongly suggesting that the variant is benign. c.79_84delAGCGGC has been reported in the literature in individuals affected with Aortic Valve Disease (Gillis_2017). This report does not provide unequivocal conclusions about association of the variant with Aortic Valve Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28659821). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2021 | Reported in a patient with bicuspid aortic valve who also harbors a variant in the NOTCH1 gene (Gillis et al., 2017); In-frame deletion of two amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32499606, 30848080, 28659821) - |
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This variant, c.79_84del, results in the deletion of 2 amino acid(s) of the SMAD6 protein (p.Ser27_Gly28del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769605183, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with SMAD6-related conditions (PMID: 28659821, 32499606). ClinVar contains an entry for this variant (Variation ID: 471762). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Aortic valve disease 2;C4479496:Craniosynostosis 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 06, 2021 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at