rs397514715
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_001127217.3(SMAD9):āc.127A>Gā(p.Lys43Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 33)
Exomes š: 0.000029 ( 0 hom. )
Consequence
SMAD9
NM_001127217.3 missense
NM_001127217.3 missense
Scores
11
6
1
Clinical Significance
Conservation
PhyloP100: 7.96
Genes affected
SMAD9 (HGNC:6774): (SMAD family member 9) The protein encoded by this gene is a member of the SMAD family, which transduces signals from TGF-beta family members. The encoded protein is activated by bone morphogenetic proteins and interacts with SMAD4. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
?
In a domain MH1 (size 124) in uniprot entity SMAD9_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_001127217.3
BS2
?
High AC in GnomAdExome4 at 43 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD9 | NM_001127217.3 | c.127A>G | p.Lys43Glu | missense_variant | 2/7 | ENST00000379826.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD9 | ENST00000379826.5 | c.127A>G | p.Lys43Glu | missense_variant | 2/7 | 5 | NM_001127217.3 | P1 | |
SMAD9 | ENST00000350148.10 | c.127A>G | p.Lys43Glu | missense_variant | 2/6 | 1 | |||
SMAD9 | ENST00000399275.7 | c.127A>G | p.Lys43Glu | missense_variant, NMD_transcript_variant | 1/6 | 1 | |||
SMAD9 | ENST00000483941.2 | n.566A>G | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000103 AC: 26AN: 251490Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135922
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727244
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74348
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Pulmonary hypertension, primary, 2 Pathogenic:1Benign:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2011 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 07, 2023 | - - |
SMAD9-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 15, 2024 | The SMAD9 c.127A>G variant is predicted to result in the amino acid substitution p.Lys43Glu. This variant has been reported in an individual with pulmonary arterial hypertension and functional studies were inconclusive as to the variant's effect on protein function (Nasim et al. 2011. PubMed ID: 21898662). This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.012);Loss of MoRF binding (P = 0.012);Loss of MoRF binding (P = 0.012);
MVP
MPC
0.97
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at