rs117185005
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_005902.4(SMAD3):c.870C>T(p.Ile290Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,611,190 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_005902.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SMAD3 | NM_005902.4 | c.870C>T | p.Ile290Ile | splice_region_variant, synonymous_variant | Exon 6 of 9 | ENST00000327367.9 | NP_005893.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0143 AC: 2176AN: 151976Hom.: 29 Cov.: 32
GnomAD3 exomes AF: 0.0155 AC: 3815AN: 246116Hom.: 39 AF XY: 0.0157 AC XY: 2100AN XY: 133952
GnomAD4 exome AF: 0.0211 AC: 30855AN: 1459100Hom.: 381 Cov.: 32 AF XY: 0.0207 AC XY: 15001AN XY: 725858
GnomAD4 genome AF: 0.0143 AC: 2176AN: 152090Hom.: 29 Cov.: 32 AF XY: 0.0136 AC XY: 1013AN XY: 74348
ClinVar
Submissions by phenotype
not specified Benign:6
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Variant summary: SMAD3 c.870C>T (p.Ile290Ile) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.016 in 246116 control chromosomes, predominantly at a frequency of 0.024 within the Non-Finnish European subpopulation in the gnomAD database, including 29 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 640 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD3 causing Aortopathy phenotype (3.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.870C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submissions (evaluation after 2014) cite the variant four times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Familial thoracic aortic aneurysm and aortic dissection Benign:5
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This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:2
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Aneurysm-osteoarthritis syndrome Benign:2
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Loeys-Dietz syndrome Benign:1
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Ehlers-Danlos syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at