rs143863014
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2
The NM_000138.5(FBN1):c.7241G>A(p.Arg2414Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,611,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.7241G>A | p.Arg2414Gln | missense_variant | 59/66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.7241G>A | p.Arg2414Gln | missense_variant | 58/65 | NP_001393645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7241G>A | p.Arg2414Gln | missense_variant | 59/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251202Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135764
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1459682Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 726304
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74388
ClinVar
Submissions by phenotype
Marfan syndrome Uncertain:3Benign:1
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces arginine with glutamine at codon 2414 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two related individuals with Marfan-related phenotype from a family with history of Marfan syndrome (PMID: 16835936). This variant has not been identified 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. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 28, 2023 | This missense variant replaces arginine with glutamine at codon 2414 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two related individuals with Marfan-related phenotype from a family with history of Marfan syndrome (PMID: 16835936). This variant has not been identified 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. - |
Stiff skin syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Weill-Marchesani syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Acromicric dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2023 | Reported in individuals with suspected TAAD or Marfan syndrome who did not meet Ghent criteria (Sakai et al., 2006; Overwater et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 22913777, 27647783, 24941995, 25812041, 25637381, 16835936, 29907982, 12938084) - |
Ectopia lentis 1, isolated, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 05, 2021 | - - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 09, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at