rs886038943
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.6430A>C(p.Asn2144His) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2144S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.6430A>C | p.Asn2144His | missense_variant | 53/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.6430A>C | p.Asn2144His | missense_variant | 52/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.6430A>C | p.Asn2144His | missense_variant | 53/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2014 | The p.N2144H variant (also known as c.6430A>C), located in coding exon 52 of the FBN1 gene, results from an A to C substitution at nucleotide position 6430. The asparagine at codon 2144 is replaced by histidine, an amino acid with some similar properties.Two other alterations at the same codon in the cbEGF-like #32 domain, p.N2144D (c.6430A>G) and p.N2144S (c.6431A>G), have been reported previously in patients with Marfan syndrome; p.N2144S (also known as p.N1246S) affects calcium binding (Comgelio P et al. Hum Mutat. 2007;28(9):928; Hewett DR et al. Hum Mol Genet. 1993;2(4):475-477).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.In the ESP, this variant was not observed in 6494 samples (12,988 alleles) with coverage at this position.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Based on the majority of available evidence to date, the p.N2144H variant is likely to be pathogenic. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2021 | ClinVar contains an entry for this variant (Variation ID: 263837). This missense change has been observed in individual(s) with Marfan syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with histidine at codon 2144 of the FBN1 protein (p.Asn2144His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn2144 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7896820, 8504310, 11829507, 12938084, 16220557, 17657824). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at