rs878853682

Variant names:

• chr15-48600147-C-T
• rs878853682
• NM_000138.5:c.434G>A
• FBN1 p.Cys145Tyr

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.434G>A​(p.Cys145Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002633099: Internal structural assessment indicates this alteration results in loss of a structural disulfide in EGF domain 2 (Yadin DA. Structure. 2013 Oct" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C145G) has been classified as Likely pathogenic. The gene FBN1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.57
• Publications: 3 publications found

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]

FBN1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Marfan syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, Genomics England PanelApp
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Specifications for FBN1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002633099: Internal structural assessment indicates this alteration results in loss of a structural disulfide in EGF domain 2 (Yadin DA. Structure. 2013 Oct;21(10):1743-56).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48600148-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 549223.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Weill-Marchesani syndrome 2, dominant, Acromicric dysplasia, isolated ectopia lentis, progeroid and marfanoid aspect-lipodystrophy syndrome, Marfan syndrome, stiff skin syndrome, Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection, ectopia lentis 1, isolated, autosomal dominant, Weill-Marchesani syndrome, neonatal Marfan syndrome, geleophysic dysplasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 15-48600147-C-T is Pathogenic according to our data. Variant chr15-48600147-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 237091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.434G>A	p.Cys145Tyr	missense	Exon 5 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.434G>A	p.Cys145Tyr	missense	Exon 4 of 65	NP_001393645.1	P35555
	FBN1	NM_001406717.1		c.434G>A	p.Cys145Tyr	missense	Exon 5 of 9	NP_001393646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.434G>A	p.Cys145Tyr	missense	Exon 5 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.434G>A		non_coding_transcript_exon	Exon 5 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.434G>A		non_coding_transcript_exon	Exon 5 of 31	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458560 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725854

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108998

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Familial thoracic aortic aneurysm and aortic dissection (2)
1	-	-	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs878853682;

hg19: chr15-48892344;

COSMIC: COSV57309709;