15-66781449-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_005585.5(SMAD6):c.1405G>A(p.Ala469Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A469P) 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>A | p.Ala469Thr | missense_variant | 4/4 | ENST00000288840.10 | |
SMAD6 | XM_011521561.3 | c.622G>A | p.Ala208Thr | missense_variant | 4/4 | ||
SMAD6 | NR_027654.2 | n.2560G>A | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.1405G>A | p.Ala469Thr | missense_variant | 4/4 | 1 | NM_005585.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1452760Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 722842
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2024 | The p.A469T variant (also known as c.1405G>A), located in coding exon 4 of the SMAD6 gene, results from a G to A substitution at nucleotide position 1405. The alanine at codon 469 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at