NM_000138.5:c.247+3A>G
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000138.5(FBN1):c.247+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000311 in 1,608,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000138.5 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- familial thoracic aortic aneurysm and aortic dissectionInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Marfan syndromeInheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
- Acromicric dysplasiaInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
- progeroid and marfanoid aspect-lipodystrophy syndromeInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
- stiff skin syndromeInheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Weill-Marchesani syndrome 2, dominantInheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- geleophysic dysplasiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- isolated ectopia lentisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- neonatal Marfan syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Weill-Marchesani syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- ectopia lentis 1, isolated, autosomal dominantInheritance: AD Classification: LIMITED Submitted by: G2P
- Shprintzen-Goldberg syndromeInheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.247+3A>G | splice_region_variant, intron_variant | Intron 3 of 65 | ENST00000316623.10 | NP_000129.3 | ||
FBN1 | NM_001406716.1 | c.247+3A>G | splice_region_variant, intron_variant | Intron 2 of 64 | NP_001393645.1 | |||
FBN1 | NM_001406717.1 | c.247+3A>G | splice_region_variant, intron_variant | Intron 3 of 8 | NP_001393646.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.247+3A>G | splice_region_variant, intron_variant | Intron 3 of 65 | 1 | NM_000138.5 | ENSP00000325527.5 | |||
FBN1 | ENST00000559133.6 | n.247+3A>G | splice_region_variant, intron_variant | Intron 3 of 66 | 1 | ENSP00000453958.2 | ||||
FBN1 | ENST00000537463.6 | n.247+3A>G | splice_region_variant, intron_variant | Intron 3 of 30 | 5 | ENSP00000440294.2 | ||||
FBN1 | ENST00000674301.2 | n.247+3A>G | splice_region_variant, intron_variant | Intron 3 of 67 | ENSP00000501333.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000804 AC: 2AN: 248874 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1456594Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 725028 show subpopulations
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152354Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74500 show subpopulations
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
This variant causes an A to G nucleotide substitution at the +3 position of intron 3 of the FBN1 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 2/248874 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 provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 928392; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at