rs199822239
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The ENST00000288840.10(SMAD6):c.973G>A(p.Ala325Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,580,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 1 hom. )
Consequence
SMAD6
ENST00000288840.10 missense
ENST00000288840.10 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 5.77
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 -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.08999571).
BS2
High AC in GnomAd4 at 22 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.973G>A | p.Ala325Thr | missense_variant | 4/4 | ENST00000288840.10 | NP_005576.3 | |
SMAD6 | XM_011521561.3 | c.190G>A | p.Ala64Thr | missense_variant | 4/4 | XP_011519863.1 | ||
SMAD6 | NR_027654.2 | n.2128G>A | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.973G>A | p.Ala325Thr | missense_variant | 4/4 | 1 | NM_005585.5 | ENSP00000288840 | P1 | |
SMAD6 | ENST00000557916.5 | c.*88G>A | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 | 1 | ENSP00000452955 | ||||
SMAD6 | ENST00000559931.5 | c.*88G>A | 3_prime_UTR_variant, NMD_transcript_variant | 4/4 | 3 | ENSP00000453446 |
Frequencies
GnomAD3 genomes AF: 0.000145 AC: 22AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000131 AC: 27AN: 205972Hom.: 0 AF XY: 0.000132 AC XY: 15AN XY: 113636
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GnomAD4 exome AF: 0.000240 AC: 343AN: 1427934Hom.: 1 Cov.: 34 AF XY: 0.000234 AC XY: 166AN XY: 708366
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GnomAD4 genome AF: 0.000145 AC: 22AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74332
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
SMAD6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 24, 2023 | The SMAD6 c.973G>A variant is predicted to result in the amino acid substitution p.Ala325Thr. This variant was reported in an individual with congenital mitral regurgitation (Tan et al. 2012. PubMed ID: 22275001). Functional studies showed that this variant does not significantly affect protein function (Tan et al. 2012. PubMed ID: 22275001; Calpena et al. 2020. PubMed ID: 32499606). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-67073355-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 325 of the SMAD6 protein (p.Ala325Thr). This variant is present in population databases (rs199822239, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital cardiovascular malformation (PMID: 22275001). ClinVar contains an entry for this variant (Variation ID: 405517). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SMAD6 function (PMID: 22275001, 32499606). 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. - |
Craniosynostosis 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 30, 2021 | ACMG classification criteria: BP4 supporting - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with congenital mitral regurgitation (Tan et al., 2012); This variant is associated with the following publications: (PMID: 32499606, 22275001) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at