rs6537355
Variant names:
Variant summary
Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_001354812.1(SMAD1):c.-177+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,142 control chromosomes in the GnomAD database, including 4,750 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.21 ( 4750 hom., cov: 31)
Exomes 𝑓: 0.091 ( 0 hom. )
Consequence
SMAD1
NM_001354812.1 intron
NM_001354812.1 intron
Scores
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -0.345
Publications
12 publications found
Genes affected
SMAD1 (HGNC:6767): (SMAD family member 1) The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signals of the bone morphogenetic proteins (BMPs), which are involved in a range of biological activities including cell growth, apoptosis, morphogenesis, development and immune responses. In response to BMP ligands, this protein can be phosphorylated and activated by the BMP receptor kinase. The phosphorylated form of this protein forms a complex with SMAD4, which is important for its function in the transcription regulation. This protein is a target for SMAD-specific E3 ubiquitin ligases, such as SMURF1 and SMURF2, and undergoes ubiquitination and proteasome-mediated degradation. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification was made for transcript
Our verdict: Benign. The variant received -12 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SMAD1 | NM_001354812.1 | c.-177+40A>G | intron_variant | Intron 1 of 6 | NP_001341741.1 | |||
| SMAD1 | XM_047415690.1 | c.-177+598A>G | intron_variant | Intron 1 of 6 | XP_047271646.1 | |||
| SMAD1 | NM_001354813.1 | c.-489A>G | upstream_gene_variant | NP_001341742.1 | ||||
| SMAD1 | NM_001354814.1 | c.-481A>G | upstream_gene_variant | NP_001341743.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SMAD1 | ENST00000514778.1 | c.-177+126A>G | intron_variant | Intron 1 of 1 | 4 | ENSP00000424959.1 | ||||
| SMAD1 | ENST00000507594.1 | c.-177+40A>G | intron_variant | Intron 1 of 1 | 4 | ENSP00000424649.1 | ||||
| SMAD1-AS2 | ENST00000658284.2 | n.193+831T>C | intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes 0.207 AC: 31415AN: 152002Hom.: 4714 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
31415
AN:
152002
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.0909 AC: 2AN: 22Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 8 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
22
Hom.:
Cov.:
0
AF XY:
AC XY:
0
AN XY:
8
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AC:
0
AN:
0
American (AMR)
AC:
0
AN:
0
Ashkenazi Jewish (ASJ)
AC:
0
AN:
0
East Asian (EAS)
AC:
0
AN:
0
South Asian (SAS)
AC:
0
AN:
0
European-Finnish (FIN)
AF:
AC:
1
AN:
6
Middle Eastern (MID)
AC:
0
AN:
0
European-Non Finnish (NFE)
AF:
AC:
1
AN:
14
Other (OTH)
AF:
AC:
0
AN:
2
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.250
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 0.207 AC: 31505AN: 152120Hom.: 4750 Cov.: 31 AF XY: 0.206 AC XY: 15348AN XY: 74390 show subpopulations
GnomAD4 genome
AF:
AC:
31505
AN:
152120
Hom.:
Cov.:
31
AF XY:
AC XY:
15348
AN XY:
74390
show subpopulations
African (AFR)
AF:
AC:
17830
AN:
41450
American (AMR)
AF:
AC:
1986
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
AC:
439
AN:
3470
East Asian (EAS)
AF:
AC:
538
AN:
5182
South Asian (SAS)
AF:
AC:
1137
AN:
4808
European-Finnish (FIN)
AF:
AC:
1199
AN:
10612
Middle Eastern (MID)
AF:
AC:
39
AN:
294
European-Non Finnish (NFE)
AF:
AC:
7762
AN:
67996
Other (OTH)
AF:
AC:
374
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
1094
2188
3283
4377
5471
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Genome Hom
Variant carriers
0
318
636
954
1272
1590
<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:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
778
AN:
3478
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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