GeneBe

rs181184476

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_005585.5(SMAD6):​c.447C>A​(p.Ala149Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000839 in 1,192,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A149A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 8.4e-7 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.862

Publications

2 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: Likely_benign. The variant received -5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 15-66703705-C-A is Benign according to our data. Variant chr15-66703705-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1740880.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-0.862 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMAD6NM_005585.5 linkc.447C>A p.Ala149Ala synonymous_variant Exon 1 of 4 ENST00000288840.10 NP_005576.3 O43541-1
SMAD6NR_027654.2 linkn.1470C>A non_coding_transcript_exon_variant Exon 1 of 5
SMAD6XR_931827.3 linkn.1470C>A 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.447C>A p.Ala149Ala synonymous_variant Exon 1 of 4 1 NM_005585.5 ENSP00000288840.5 O43541-1
SMAD6ENST00000557916.5 linkn.447C>A non_coding_transcript_exon_variant Exon 1 of 5 1 ENSP00000452955.1 O43541-4
SMAD6ENST00000612349.1 linkn.629C>A non_coding_transcript_exon_variant Exon 1 of 1 6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
8.39e-7
AC:
1
AN:
1192260
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
582884
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
25050
American (AMR)
AF:
0.00
AC:
0
AN:
22402
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18316
East Asian (EAS)
AF:
0.0000406
AC:
1
AN:
24656
South Asian (SAS)
AF:
0.00
AC:
0
AN:
48628
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
35642
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4436
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
966388
Other (OTH)
AF:
0.00
AC:
0
AN:
46742
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: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Benign:1
Aug 03, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
CADD
Benign
11
DANN
Benign
0.77
PhyloP100
-0.86
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

dbSNP: rs181184476; hg19: chr15-66996043; API