rs140598

Variant names:

• chr15-48487333-G-C
• rs140598
• NM_000138.5:c.3442C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-48487333-G-C
• chr15-48487333-G-A
• chr15-48487333-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.3442C>G​(p.Pro1148Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,216 control chromosomes in the GnomAD database, including 1,844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1148L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (207 hom., cov: 32)
  • Exomes 𝑓: 0.012 (1637 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 1.29
• Publications: 47 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Genomics England PanelApp
• 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: Ambry Genetics, Orphanet
• progeroid and marfanoid aspect-lipodystrophy syndrome

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

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_000138.5
• 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 Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017159283).
• BP6: Variant 15-48487333-G-C is Benign according to our data. Variant chr15-48487333-G-C is described in ClinVar as Benign. ClinVar VariationId is 36065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

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.3442C>G	p.Pro1148Ala	missense	Exon 28 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.3442C>G	p.Pro1148Ala	missense	Exon 27 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.3442C>G	p.Pro1148Ala	missense	Exon 28 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.3442C>G		non_coding_transcript_exon	Exon 28 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.3442C>G		non_coding_transcript_exon	Exon 28 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2559 AN: 152218 Hom.: 205 Cov.: 32

Gnomad AFR AF: 0.00856

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0316 AC: 7939 AN: 251466 AF XY: 0.0281

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0722

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.240

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0118 AC: 17271 AN: 1461880 Hom.: 1637 Cov.: 32 AF XY: 0.0116 AC XY: 8426 AN XY: 727244

African (AFR) AF: 0.00797 AC: 267 AN: 33480

American (AMR) AF: 0.0703 AC: 3144 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.260 AC: 10329 AN: 39700

South Asian (SAS) AF: 0.0157 AC: 1358 AN: 86258

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53410

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.000763 AC: 848 AN: 1112008

Other (OTH) AF: 0.0181 AC: 1091 AN: 60396

GnomAD4 genome AF: 0.0169 AC: 2569 AN: 152336 Hom.: 207 Cov.: 32 AF XY: 0.0195 AC XY: 1452 AN XY: 74496

African (AFR) AF: 0.00856 AC: 356 AN: 41586

American (AMR) AF: 0.0471 AC: 721 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.241 AC: 1245 AN: 5174

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4828

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000999 AC: 68 AN: 68038

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.00977 Hom.: 103

Bravo AF: 0.0214

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00887 AC: 39

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.0288 AC: 3497

Asia WGS AF: 0.117 AC: 404 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	4	Marfan syndrome (4)
-	-	2	not provided (2)
-	-	1	Acromicric dysplasia (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Ectopia lentis 1, isolated, autosomal dominant (1)
-	-	1	FNB1 POLYMORPHISM (1)
-	-	1	Geleophysic dysplasia (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Stiff skin syndrome (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.074
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.47
Sift	Benign	0.30	T
Sift4G	Benign	0.39	T
Vest4		0.10
MPC		1.2
ClinPred		0.037	T
GERP RS		5.6
Mutation Taster		=42/58	polymorphism (auto)

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

Other links and lift over

dbSNP: rs140598; hg19: chr15-48779530; COSMIC: COSV57317550;