rs775257418

chr15-48492594-G-Achr15-48492594-G-Cchr15-48492594-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000138.5(FBN1):c.2729-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBN1 NM_000138.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005031
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-48492594-G-A is Benign according to our data. Variant chr15-48492594-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 527226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.2729-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.2729-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.2729-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 12 AN: 149462 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000811

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000629 AC: 143 AN: 227452 Hom.: 0 AF XY: 0.000525 AC XY: 65 AN XY: 123896

Gnomad AFR exome AF: 0.000348

Gnomad AMR exome AF: 0.000227

Gnomad ASJ exome AF: 0.000756

Gnomad EAS exome AF: 0.000366

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000672

Gnomad NFE exome AF: 0.000786

Gnomad OTH exome AF: 0.00129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000149 AC: 210 AN: 1406438 Hom.: 0 Cov.: 26 AF XY: 0.000150 AC XY: 105 AN XY: 701926

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.000276

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.000219

Gnomad4 FIN exome AF: 0.000246

Gnomad4 NFE exome AF: 0.0000944

Gnomad4 OTH exome AF: 0.000344

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000803 AC: 12 AN: 149462 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 9 AN XY: 72766

Gnomad4 AFR AF: 0.0000492

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000811

Gnomad4 NFE AF: 0.0000297

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00684 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.8
Dann	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775257418; hg19: chr15-48784791;