chr4-145539950-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005900.3(SMAD1):​c.547C>G​(p.Pro183Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,758 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P183L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SMAD1
NM_005900.3 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14744559).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMAD1NM_005900.3 linkc.547C>G p.Pro183Ala missense_variant Exon 3 of 7 ENST00000302085.9 NP_005891.1 Q15797-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMAD1ENST00000302085.9 linkc.547C>G p.Pro183Ala missense_variant Exon 3 of 7 1 NM_005900.3 ENSP00000305769.4 Q15797-1
SMAD1ENST00000394092.6 linkc.547C>G p.Pro183Ala missense_variant Exon 3 of 7 1 ENSP00000377652.2 Q15797-1
SMAD1ENST00000515385.1 linkc.547C>G p.Pro183Ala missense_variant Exon 3 of 7 2 ENSP00000426568.1 Q15797-1
SMAD1ENST00000502342.1 linkn.243C>G non_coding_transcript_exon_variant Exon 2 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461758
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.547C>G (p.P183A) alteration is located in exon 3 (coding exon 2) of the SMAD1 gene. This alteration results from a C to G substitution at nucleotide position 547, causing the proline (P) at amino acid position 183 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
0.0
CADD
Benign
20
DANN
Benign
0.90
DEOGEN2
Benign
0.39
T;T;T
Eigen
Benign
-0.12
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.81
.;.;T
M_CAP
Uncertain
0.089
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Uncertain
0.21
D
MutationAssessor
Benign
1.7
L;L;L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
0.83
N;N;N
REVEL
Uncertain
0.44
Sift
Benign
1.0
T;T;T
Sift4G
Benign
0.62
T;T;T
Polyphen
0.0010
B;B;B
Vest4
0.27
MutPred
0.13
Loss of glycosylation at P183 (P = 0.0516);Loss of glycosylation at P183 (P = 0.0516);Loss of glycosylation at P183 (P = 0.0516);
MVP
0.66
MPC
0.10
ClinPred
0.66
D
GERP RS
6.0
Varity_R
0.068
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-146461102; API