15-48644604-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Moderate

The NM_000138.5(FBN1):c.164+2T>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.16

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.03992572 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-48644604-A-G is Pathogenic according to our data. Variant chr15-48644604-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163485.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.164+2T>C		splice_donor_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.164+2T>C		splice_donor_variant
FBN1	NM_001406717.1	c.164+2T>C		splice_donor_variant
FBN1	NM_001406718.1	c.164+2T>C		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.164+2T>C		splice_donor_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 23, 2013

The 164+2T>C variant in FBN1 has not been previously reported in individuals wit h Marfan syndrome or in large population studies. However, another variant (164+ 1G>A) affecting the same donor splice site has been identified in a patient with an incomplete form of Marfan syndrome (Comeglio 2007). This variant occurs in t he invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;N
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503058; hg19: chr15-48936801;