chr15-66781042-G-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_005585.5(SMAD6):āc.998G>Cā(p.Ser333Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,600,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S333N) has been classified as Uncertain significance.
Frequency
Consequence
NM_005585.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.998G>C | p.Ser333Thr | missense_variant | 4/4 | ENST00000288840.10 | |
SMAD6 | XM_011521561.3 | c.215G>C | p.Ser72Thr | missense_variant | 4/4 | ||
SMAD6 | NR_027654.2 | n.2153G>C | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.998G>C | p.Ser333Thr | missense_variant | 4/4 | 1 | NM_005585.5 | P1 | |
SMAD6 | ENST00000557916.5 | c.*113G>C | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 | 1 | ||||
SMAD6 | ENST00000559931.5 | c.*113G>C | 3_prime_UTR_variant, NMD_transcript_variant | 4/4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000104 AC: 24AN: 229762Hom.: 0 AF XY: 0.000103 AC XY: 13AN XY: 126044
GnomAD4 exome AF: 0.000198 AC: 287AN: 1448226Hom.: 0 Cov.: 34 AF XY: 0.000174 AC XY: 125AN XY: 720434
GnomAD4 genome AF: 0.000177 AC: 27AN: 152362Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74502
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with craniosynostosis in published literature; however, the variant did not appear to negatively affect SMAD6 inhibitory function on luciferase assay (Calpena et al., 2020); This variant is associated with the following publications: (PMID: 32499606) - |
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 333 of the SMAD6 protein (p.Ser333Thr). This variant is present in population databases (rs199531653, gnomAD 0.02%). This missense change has been observed in individual(s) with craniosynostosis (PMID: 32499606). ClinVar contains an entry for this variant (Variation ID: 471766). 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: 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at