15-66703536-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4_ModerateBS2
The NM_005585.5(SMAD6):āc.278T>Cā(p.Met93Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,221,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M93I) has been classified as Uncertain significance.
Frequency
Consequence
NM_005585.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.278T>C | p.Met93Thr | missense_variant | 1/4 | ENST00000288840.10 | |
SMAD6 | NR_027654.2 | n.1301T>C | non_coding_transcript_exon_variant | 1/5 | |||
SMAD6 | XR_931827.3 | n.1301T>C | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.278T>C | p.Met93Thr | missense_variant | 1/4 | 1 | NM_005585.5 | P1 | |
SMAD6 | ENST00000557916.5 | c.278T>C | p.Met93Thr | missense_variant, NMD_transcript_variant | 1/5 | 1 | |||
SMAD6 | ENST00000612349.1 | n.460T>C | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000530 AC: 8AN: 150992Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000393 AC: 42AN: 1070042Hom.: 0 Cov.: 31 AF XY: 0.0000494 AC XY: 25AN XY: 506452
GnomAD4 genome ? AF: 0.0000530 AC: 8AN: 150992Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1AN XY: 73750
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 31, 2023 | The p.M93T variant (also known as c.278T>C), located in coding exon 1 of the SMAD6 gene, results from a T to C substitution at nucleotide position 278. The methionine at codon 93 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 93 of the SMAD6 protein (p.Met93Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 405514). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at