rs113001196

Variant names:

• chr15-48432947-G-A
• rs113001196
• NM_000138.5:c.6658C>T
• FBN1 p.Arg2220*

Your query was ambiguous. Multiple possible variants found:

• chr15-48432947-G-A
• chr15-48432947-G-C

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_000138.5(FBN1):c.6658C>T (p.Arg2220*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,324 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000009. In-silico predictor (BayesDel (addAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 10.0
• Publications: 5 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):

• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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: Labcorp Genetics (formerly Invitae), G2P
• 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

Classification according to ACMG Germline Pathogenicity v2019

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

Our verdict: Pathogenic. The variant received 14 points.

• PVS1: Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 55 of 66) at amino acid 2220 of 2871, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000009 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (13/13 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.6658C>T	p.Arg2220*	stop_gained	Exon 55 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.6658C>T	p.Arg2220*	stop_gained	Exon 54 of 65	NP_001393645.1	P35555

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.6658C>T	p.Arg2220*	stop_gained	Exon 55 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.6658C>T		non_coding_transcript_exon	Exon 55 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.*2421C>T		3_prime_UTR	Exon 30 of 31	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461324 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726982

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111582

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Marfan syndrome (6)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Isolated thoracic aortic aneurysm (1)
1	-	-	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections (1)
1	-	-	not provided (1)
1	-	-	not specified (1)
1	-	-	Thoracic aortic aneurysm or dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		10
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs113001196;

hg19: chr15-48725144;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar