rs397515753
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.1051C>T(p.Gln351*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000138.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1051C>T | p.Gln351* | stop_gained | Exon 10 of 66 | 1 | NM_000138.5 | ENSP00000325527.5 | ||
FBN1 | ENST00000559133.6 | n.1051C>T | non_coding_transcript_exon_variant | Exon 10 of 67 | 1 | ENSP00000453958.2 | ||||
FBN1 | ENST00000674301.2 | n.1051C>T | non_coding_transcript_exon_variant | Exon 10 of 68 | ENSP00000501333.2 | |||||
FBN1 | ENST00000537463.6 | n.636+16956C>T | intron_variant | Intron 7 of 30 | 5 | ENSP00000440294.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:1
The Gln351X variant in FBN1 has been reported in one individual with clinical fe atures of Marfan syndrome (Comeglio 2007). This nonsense variant leads to a prem ature termination codon at position 351, which is predicted to lead to a truncat ed or absent protein. Heterozygous loss of function of the FBN1 gene is an estab lished disease mechanism in Marfan syndrome. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42280). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 17657824, 24199744). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln351*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at