chr15-66703266-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005585.5(SMAD6):​c.8G>A​(p.Arg3Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000102 in 1,477,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R3S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.30

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMAD6NM_005585.5 linkc.8G>A p.Arg3Lys missense_variant Exon 1 of 4 ENST00000288840.10 NP_005576.3 O43541-1
SMAD6NR_027654.2 linkn.1031G>A non_coding_transcript_exon_variant Exon 1 of 5
SMAD6XR_931827.3 linkn.1031G>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.8G>A p.Arg3Lys missense_variant Exon 1 of 4 1 NM_005585.5 ENSP00000288840.5 O43541-1
SMAD6ENST00000557916.5 linkn.8G>A non_coding_transcript_exon_variant Exon 1 of 5 1 ENSP00000452955.1 O43541-4
SMAD6ENST00000612349.1 linkn.190G>A non_coding_transcript_exon_variant Exon 1 of 1 6

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000981
AC:
13
AN:
1325352
Hom.:
0
Cov.:
31
AF XY:
0.00000764
AC XY:
5
AN XY:
654636
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26588
American (AMR)
AF:
0.00
AC:
0
AN:
25304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
22928
East Asian (EAS)
AF:
0.00
AC:
0
AN:
28866
South Asian (SAS)
AF:
0.00
AC:
0
AN:
71486
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47114
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4106
European-Non Finnish (NFE)
AF:
0.0000124
AC:
13
AN:
1044992
Other (OTH)
AF:
0.00
AC:
0
AN:
53968
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.517
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74292
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41420
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10578
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
67984
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 23, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.8G>A (p.R3K) alteration is located in exon 1 (coding exon 1) of the SMAD6 gene. This alteration results from a G to A substitution at nucleotide position 8, causing the arginine (R) at amino acid position 3 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Aortic valve disease 2 Uncertain:1
Oct 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 3 of the SMAD6 protein (p.Arg3Lys). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1047455). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
AlphaMissense
Pathogenic
0.73
BayesDel_addAF
Benign
-0.025
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.74
T
M_CAP
Pathogenic
0.52
D
MetaRNN
Uncertain
0.44
T
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Benign
0.90
L
PhyloP100
5.3
PrimateAI
Pathogenic
0.94
D
PROVEAN
Benign
-0.69
N
REVEL
Uncertain
0.35
Sift
Benign
0.25
T
Sift4G
Benign
0.25
T
Polyphen
0.98
D
Vest4
0.20
MutPred
0.35
Gain of methylation at R3 (P = 0.0158);
MVP
0.75
MPC
1.2
ClinPred
0.87
D
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.27
gMVP
0.42
Mutation Taster
=55/45
polymorphism

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: rs1337502697; hg19: chr15-66995604; API