chr15-48468097-G-A

Variant names:

• chr15-48468097-G-A
• rs111401431
• NM_000138.5:c.4588C>T
• FBN1 p.Arg1530Cys

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP2PP3_ModeratePP5_Strong

The NM_000138.5(FBN1):c.4588C>T (p.Arg1530Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,832 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R1530L: Likely_pathogenic (ClinVar VariationId 2134989, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1530H: Uncertain_significance (ClinVar VariationId 926280, 2 stars); p.R1530S: Uncertain_significance (ClinVar VariationId 918685, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 6.62
• Publications: 10 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.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 8 pathogenic, 0 benign (OR vs. background: 85.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R1530L: Likely_pathogenic (ClinVar VariationId 2134989, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R1530H: Uncertain_significance (ClinVar VariationId 926280, 2 stars); p.R1530S: Uncertain_significance (ClinVar VariationId 918685, 1 star)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 8.199). ClinVar shows strong pathogenic missense enrichment: 1744 P/LP and 288 B/LB missense entries (ratio 6.1×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		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 (19/19 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.4588C>T p.Arg1530Cys	missense	Exon 38 of 66	Prot: NP_000129.3
	FBN1 NM_001406716.1		c.4588C>T p.Arg1530Cys	missense	Exon 37 of 65	Prot: NP_001393645.1 UniProt:

FBN1 NM_000138.5

MANE Select

HGVSc / HGVSpc.4588C>Tp.Arg1530Cys

Exon rankExon 38 of 66

missense

Prot: NP_000129.3

FBN1 NM_001406716.1

HGVSc / HGVSpc.4588C>Tp.Arg1530Cys

Exon rankExon 37 of 65

missense

Prot: NP_001393645.1UniProt: P35555

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FBN1 ENST00000316623.10	TSL:1MANE Select	c.4588C>T p.Arg1530Cys	missense	Exon 38 of 66	Prot: ENSP00000325527.5 UniProt:
	FBN1 ENST00000559133.6	TSL:1	n.4588C>T	non_coding_transcript_exon	Exon 38 of 67	Prot: ENSP00000453958.2 UniProt:
	FBN1 ENST00000537463.6	TSL:5	n.*351C>T	3_prime_UTR	Exon 13 of 31	Prot: ENSP00000440294.2 UniProt:

FBN1 ENST00000316623.10

TSL:1MANE Select

HGVSc / HGVSpc.4588C>Tp.Arg1530Cys

Exon rankExon 38 of 66

missense

Prot: ENSP00000325527.5UniProt: P35555

FBN1 ENST00000559133.6

TSL:1

HGVSc / HGVSpn.4588C>T

Exon rankExon 38 of 67

non_coding_transcript_exon

Prot: ENSP00000453958.2UniProt: H0YND0

FBN1 ENST00000537463.6

TSL:5

HGVSc / HGVSpn.*351C>T

Exon rankExon 13 of 31

3_prime_UTR

Prot: ENSP00000440294.2UniProt: F6U495

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461832	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:190730	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
6	-	-	Marfan syndrome (6)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	FBN1-related disorder (1)
1	-	-	Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome (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)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	31
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-9.0
GPN-Star score	N/A	9.0
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.94	D
Mutation Taster	N/A	22/78	disease causing (ClinVar)
PhyloP100	Uncertain	6.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.043	D
VESM-3B	Benign	-14

Showing 24 of 24 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs111401431;

hg19: chr15-48760294;

COSMIC: COSV57310752;

COSMIC: COSV57310752;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar