rs375721252
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_000138.5(FBN1):c.538+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,613,396 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000138.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FBN1 | NM_000138.5 | c.538+4A>G | splice_region_variant, intron_variant | Intron 6 of 65 | ENST00000316623.10 | NP_000129.3 | ||
| FBN1 | NM_001406716.1 | c.538+4A>G | splice_region_variant, intron_variant | Intron 5 of 64 | NP_001393645.1 | |||
| FBN1 | NM_001406717.1 | c.538+4A>G | splice_region_variant, intron_variant | Intron 6 of 8 | NP_001393646.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FBN1 | ENST00000316623.10 | c.538+4A>G | splice_region_variant, intron_variant | Intron 6 of 65 | 1 | NM_000138.5 | ENSP00000325527.5 | |||
| FBN1 | ENST00000559133.6 | n.538+4A>G | splice_region_variant, intron_variant | Intron 6 of 66 | 1 | ENSP00000453958.2 | ||||
| FBN1 | ENST00000537463.6 | n.538+4A>G | splice_region_variant, intron_variant | Intron 6 of 30 | 5 | ENSP00000440294.2 | ||||
| FBN1 | ENST00000674301.2 | n.538+4A>G | splice_region_variant, intron_variant | Intron 6 of 67 | ENSP00000501333.2 |
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000338 AC: 85AN: 251336Hom.: 1 AF XY: 0.000456 AC XY: 62AN XY: 135844
GnomAD4 exome AF: 0.000181 AC: 265AN: 1461106Hom.: 2 Cov.: 31 AF XY: 0.000282 AC XY: 205AN XY: 726912
GnomAD4 genome 0.000125 AC: 19AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74460
ClinVar
Submissions by phenotype
not provided Benign:4
FBN1: BS1 -
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Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:2
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Benign:1
Variant summary: FBN1 c.538+4A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict an impact on normal splicing: Three predict the variant weakens a 5' donor site. Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00033 in 246094 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 20-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.538+4A>G in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. -
Marfan syndrome Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Stiff skin syndrome Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Weill-Marchesani syndrome Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Geleophysic dysplasia Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Acromicric dysplasia Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
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Ectopia lentis 1, isolated, autosomal dominant Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Connective tissue disorder Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at