15-48516335-G-C
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_000138.5(FBN1):āc.1175C>Gā(p.Pro392Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,816 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P392L) has been classified as Likely benign.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1175C>G | p.Pro392Arg | missense_variant | Exon 11 of 66 | 1 | NM_000138.5 | ENSP00000325527.5 | ||
FBN1 | ENST00000559133.6 | n.1175C>G | non_coding_transcript_exon_variant | Exon 11 of 67 | 1 | ENSP00000453958.2 | ||||
FBN1 | ENST00000674301.2 | n.1175C>G | non_coding_transcript_exon_variant | Exon 11 of 68 | ENSP00000501333.2 | |||||
FBN1 | ENST00000537463.6 | n.636+21376C>G | intron_variant | Intron 7 of 30 | 5 | ENSP00000440294.2 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 250242Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135402
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461586Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727108
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74436
ClinVar
Submissions by phenotype
Marfan syndrome Uncertain:1
This missense variant replaces proline with arginine at codon 392 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with unexplained sudden cardiac death (PMID: 25447171). This variant has been identified in 8/250242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
Variant summary: FBN1 c.1175C>G (p.Pro392Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250242 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1175C>G has been reported in the literature in an individual who died of sudden cardiac death, with no-conclusive cause (Campuzano_2014). This report does not provide an unequivocal conclusion about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at