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

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 start_lost

Scores

7
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.04

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
Start lost variant, next in-frame start position is after 27 pathogenic variants. Next in-frame start position is after 93 codons. Genomic position: 66703535. Lost 0.186 part of the original CDS.
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.1A>G p.Met1? start_lost Exon 1 of 4 ENST00000288840.10 NP_005576.3 O43541-1
SMAD6NR_027654.2 linkn.1024A>G non_coding_transcript_exon_variant Exon 1 of 5
SMAD6XR_931827.3 linkn.1024A>G 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.1A>G p.Met1? start_lost Exon 1 of 4 1 NM_005585.5 ENSP00000288840.5 O43541-1
SMAD6ENST00000557916.5 linkn.1A>G non_coding_transcript_exon_variant Exon 1 of 5 1 ENSP00000452955.1 O43541-4
SMAD6ENST00000612349.1 linkn.183A>G non_coding_transcript_exon_variant Exon 1 of 1 6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000231
AC:
3
AN:
1300550
Hom.:
0
Cov.:
31
AF XY:
0.00000468
AC XY:
3
AN XY:
641674
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
25752
American (AMR)
AF:
0.00
AC:
0
AN:
21344
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
22042
East Asian (EAS)
AF:
0.00
AC:
0
AN:
28556
South Asian (SAS)
AF:
0.00
AC:
0
AN:
67354
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46322
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3920
European-Non Finnish (NFE)
AF:
0.00000291
AC:
3
AN:
1032590
Other (OTH)
AF:
0.00
AC:
0
AN:
52670
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

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
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
Mar 16, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.53
D
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.095
D
PhyloP100
2.0
PROVEAN
Benign
-1.5
N
REVEL
Pathogenic
0.67
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.92
P
Vest4
0.91
MutPred
0.98
Gain of methylation at K5 (P = 0.1521);
MVP
0.76
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.95
gMVP
0.61
Mutation Taster
=9/191
disease causing

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: chr15-66995597; API