15-66781449-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_005585.5(SMAD6):āc.1405G>Cā(p.Ala469Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,760 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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A469T) 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_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.1405G>C | p.Ala469Pro | missense_variant | 4/4 | ENST00000288840.10 | |
SMAD6 | XM_011521561.3 | c.622G>C | p.Ala208Pro | missense_variant | 4/4 | ||
SMAD6 | NR_027654.2 | n.2560G>C | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.1405G>C | p.Ala469Pro | missense_variant | 4/4 | 1 | NM_005585.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1452760Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 722842
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2017 | This variant has not been reported in the literature in individuals with SMAD6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 469 of the SMAD6 protein (p.Ala469Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. 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