NM_005585.5:c.24delG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_005585.5(SMAD6):c.24delG(p.Leu9TrpfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.5e-7 ( 0 hom. )
Consequence
SMAD6
NM_005585.5 frameshift
NM_005585.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.694
Publications
1 publications found
Genes affected
SMAD6 (HGNC:6772): (SMAD family member 6) The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]
SMAD6 Gene-Disease associations (from GenCC):
- 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
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 101 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-66703278-CG-C is Pathogenic according to our data. Variant chr15-66703278-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1174563.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SMAD6 | NM_005585.5 | c.24delG | p.Leu9TrpfsTer55 | frameshift_variant | Exon 1 of 4 | ENST00000288840.10 | NP_005576.3 | |
| SMAD6 | NR_027654.2 | n.1047delG | non_coding_transcript_exon_variant | Exon 1 of 5 | ||||
| SMAD6 | XR_931827.3 | n.1047delG | 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.24delG | p.Leu9TrpfsTer55 | frameshift_variant | Exon 1 of 4 | 1 | NM_005585.5 | ENSP00000288840.5 | ||
| SMAD6 | ENST00000557916.5 | n.24delG | non_coding_transcript_exon_variant | Exon 1 of 5 | 1 | ENSP00000452955.1 | ||||
| SMAD6 | ENST00000612349.1 | n.206delG | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 7.50e-7 AC: 1AN: 1333248Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1AN XY: 658624 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1333248
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
658624
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
26760
American (AMR)
AF:
AC:
0
AN:
26212
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
23162
East Asian (EAS)
AF:
AC:
0
AN:
29020
South Asian (SAS)
AF:
AC:
1
AN:
72560
European-Finnish (FIN)
AF:
AC:
0
AN:
47362
Middle Eastern (MID)
AF:
AC:
0
AN:
4224
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1049496
Other (OTH)
AF:
AC:
0
AN:
54452
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Radioulnar synostosis Pathogenic:1
Jun 20, 2020
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.