GeneBe

15-66703282-GC-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_005585.5(SMAD6):​c.25delC​(p.Leu9TrpfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L9L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

Publications

0 publications found
Variant links:
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 7
    Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
  • radioulnar synostosis, nonsyndromic, susceptibility to
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
  • aortic valve disease 2
    Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
  • familial bicuspid aortic valve
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital radioulnar synostosis
    Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
  • congenital heart defects, multiple types
    Inheritance: 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 10 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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMAD6NM_005585.5 linkc.25delC p.Leu9TrpfsTer55 frameshift_variant Exon 1 of 4 ENST00000288840.10 NP_005576.3 O43541-1
SMAD6NR_027654.2 linkn.1048delC non_coding_transcript_exon_variant Exon 1 of 5
SMAD6XR_931827.3 linkn.1048delC non_coding_transcript_exon_variant Exon 1 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMAD6ENST00000288840.10 linkc.25delC p.Leu9TrpfsTer55 frameshift_variant Exon 1 of 4 1 NM_005585.5 ENSP00000288840.5 O43541-1
SMAD6ENST00000557916.5 linkn.25delC non_coding_transcript_exon_variant Exon 1 of 5 1 ENSP00000452955.1 O43541-4
SMAD6ENST00000612349.1 linkn.207delC non_coding_transcript_exon_variant Exon 1 of 1 6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.47e-7
AC:
1
AN:
1338290
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
661000
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26996
American (AMR)
AF:
0.00
AC:
0
AN:
27318
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23378
East Asian (EAS)
AF:
0.00
AC:
0
AN:
29088
South Asian (SAS)
AF:
0.0000136
AC:
1
AN:
73330
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47424
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4258
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1051754
Other (OTH)
AF:
0.00
AC:
0
AN:
54744
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
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
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Aortic valve disease 2 Uncertain:1
Sep 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Leu9Trpfs*55) in the SMAD6 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SMAD6 cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

hg19: chr15-66995620; API