15-66703278-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_005585.5(SMAD6):c.20C>A(p.Ser7Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000015 in 1,333,252 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 (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000015 ( 0 hom. )
Consequence
SMAD6
NM_005585.5 stop_gained
NM_005585.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.74
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 Pathogenic. Variant got 10 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.20C>A | p.Ser7Ter | stop_gained | 1/4 | ENST00000288840.10 | NP_005576.3 | |
SMAD6 | NR_027654.2 | n.1043C>A | non_coding_transcript_exon_variant | 1/5 | ||||
SMAD6 | XR_931827.3 | n.1043C>A | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.20C>A | p.Ser7Ter | stop_gained | 1/4 | 1 | NM_005585.5 | ENSP00000288840 | P1 | |
SMAD6 | ENST00000557916.5 | c.20C>A | p.Ser7Ter | stop_gained, NMD_transcript_variant | 1/5 | 1 | ENSP00000452955 | |||
SMAD6 | ENST00000612349.1 | n.202C>A | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000150 AC: 2AN: 1333252Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1AN XY: 658624
GnomAD4 exome
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2
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1333252
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31
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1
AN XY:
658624
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 05, 2023 | This sequence change creates a premature translational stop signal (p.Ser7*) in the SMAD6 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SMAD6 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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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