chr15-66704034-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting
The NM_005585.5(SMAD6):āc.776T>Cā(p.Val259Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000575 in 1,513,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000039 ( 0 hom., cov: 33)
Exomes š: 0.000059 ( 0 hom. )
Consequence
SMAD6
NM_005585.5 missense
NM_005585.5 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 5.61
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 Uncertain_significance. Variant got 1 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.857
BS2
High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.776T>C | p.Val259Ala | missense_variant | 1/4 | ENST00000288840.10 | |
SMAD6 | NR_027654.2 | n.1799T>C | non_coding_transcript_exon_variant | 1/5 | |||
SMAD6 | XR_931827.3 | n.1799T>C | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.776T>C | p.Val259Ala | missense_variant | 1/4 | 1 | NM_005585.5 | P1 | |
SMAD6 | ENST00000557916.5 | c.776T>C | p.Val259Ala | missense_variant, NMD_transcript_variant | 1/5 | 1 | |||
SMAD6 | ENST00000612349.1 | n.958T>C | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152118Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000595 AC: 81AN: 1361562Hom.: 0 Cov.: 32 AF XY: 0.0000489 AC XY: 33AN XY: 675262
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152118Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3Other:1
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 | Jul 30, 2023 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2022 | The p.V259A variant (also known as c.776T>C), located in coding exon 1 of the SMAD6 gene, results from a T to C substitution at nucleotide position 776. The valine at codon 259 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2021 | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 259 of the SMAD6 protein (p.Val259Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 579137). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 09-25-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of disorder (P = 0.0348);
MVP
MPC
ClinPred
D
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