chr15-48468095-GCG-ACA

Variant names:

• chr15-48468095-GCG-ACA
• NM_000138.5:c.4588_4590delCGCinsTGT
• FBN1 p.Arg1530Cys

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 15 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5PP2

The NM_000138.5(FBN1):c.4588_4590delCGCinsTGT (p.Arg1530Cys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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 15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	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		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (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×).

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.4588_4590delCGCinsTGT p.Arg1530Cys	missense	N/A	Prot: NP_000129.3
	FBN1 NM_001406716.1		c.4588_4590delCGCinsTGT p.Arg1530Cys	missense	N/A	Prot: NP_001393645.1 UniProt:

FBN1 NM_000138.5

MANE Select

HGVSc / HGVSpc.4588_4590delCGCinsTGTp.Arg1530Cys

Exon rankN/A

missense

Prot: NP_000129.3

FBN1 NM_001406716.1

HGVSc / HGVSpc.4588_4590delCGCinsTGTp.Arg1530Cys

Exon rankN/A

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.4588_4590delCGCinsTGT p.Arg1530Cys	missense	N/A	Prot: ENSP00000325527.5 UniProt:
	FBN1 ENST00000559133.6	TSL:1	n.4588_4590delCGCinsTGT	non_coding_transcript_exon	Exon 38 of 67	Prot: ENSP00000453958.2 UniProt:
	FBN1 ENST00000537463.6	TSL:5	n.*351_*353delCGCinsTGT	3_prime_UTR	Exon 13 of 31	Prot: ENSP00000440294.2 UniProt:

FBN1 ENST00000316623.10

TSL:1MANE Select

HGVSc / HGVSpc.4588_4590delCGCinsTGTp.Arg1530Cys

Exon rankN/A

missense

Prot: ENSP00000325527.5UniProt: P35555

FBN1 ENST00000559133.6

TSL:1

HGVSc / HGVSpn.4588_4590delCGCinsTGT

Exon rankExon 38 of 67

non_coding_transcript_exon

Prot: ENSP00000453958.2UniProt: H0YND0

FBN1 ENST00000537463.6

TSL:5

HGVSc / HGVSpn.*351_*353delCGCinsTGT

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr15-48760292;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar