chr15-66703259-A-G
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_005585.5(SMAD6):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000231 in 1,300,550 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
Consequence
NM_005585.5 start_lost
Scores
Clinical Significance
Conservation
Publications
- craniosynostosis 7Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
- radioulnar synostosis, nonsyndromic, susceptibility toInheritance: AD Classification: STRONG Submitted by: Ambry Genetics
- aortic valve disease 2Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- familial bicuspid aortic valveInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- congenital radioulnar synostosisInheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
- congenital heart defects, multiple typesInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.1A>G | p.Met1? | start_lost | Exon 1 of 4 | ENST00000288840.10 | NP_005576.3 | |
SMAD6 | NR_027654.2 | n.1024A>G | non_coding_transcript_exon_variant | Exon 1 of 5 | ||||
SMAD6 | XR_931827.3 | n.1024A>G | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.1A>G | p.Met1? | start_lost | Exon 1 of 4 | 1 | NM_005585.5 | ENSP00000288840.5 | ||
SMAD6 | ENST00000557916.5 | n.1A>G | non_coding_transcript_exon_variant | Exon 1 of 5 | 1 | ENSP00000452955.1 | ||||
SMAD6 | ENST00000612349.1 | n.183A>G | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000231 AC: 3AN: 1300550Hom.: 0 Cov.: 31 AF XY: 0.00000468 AC XY: 3AN XY: 641674 show subpopulations
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Aortic valve disease 2 Uncertain:1
Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. Disruption of the initiator codon has been observed in individual(s) with craniosynostosis (PMID: 28808027). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SMAD6 mRNA. The next in-frame methionine is located at codon 93. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at