rs363832

Variant names:

• chr15-48428329-G-C
• rs363832
• NM_000138.5:c.6997+17C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-48428329-G-C
• chr15-48428329-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.6997+17C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 1,613,274 control chromosomes in the GnomAD database, including 463,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36747 hom., cov: 31)
  • Exomes 𝑓: 0.76 (426632 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.539
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-48428329-G-C is Benign according to our data. Variant chr15-48428329-G-C is described in ClinVar as Benign. ClinVar VariationId is 137312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.782 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.6997+17C>G		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.6997+17C>G		intron	N/A	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.6997+17C>G		intron	N/A	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.6997+17C>G		intron	N/A	ENSP00000453958.2	H0YND0
	FBN1	ENST00000682170.1		n.623C>G		non_coding_transcript_exon	Exon 5 of 13

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103792 AN: 151924 Hom.: 36741 Cov.: 31

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.734

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.702

GnomAD2 exomes AF: 0.746 AC: 186984 AN: 250584 AF XY: 0.754

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.791

Gnomad ASJ exome AF: 0.806

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.744

Gnomad NFE exome AF: 0.767

Gnomad OTH exome AF: 0.760

GnomAD4 exome AF: 0.762 AC: 1113337 AN: 1461232 Hom.: 426632 Cov.: 47 AF XY: 0.764 AC XY: 555546 AN XY: 726914

African (AFR) AF: 0.464 AC: 15536 AN: 33460

American (AMR) AF: 0.784 AC: 35058 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 21022 AN: 26124

East Asian (EAS) AF: 0.658 AC: 26119 AN: 39668

South Asian (SAS) AF: 0.812 AC: 70024 AN: 86240

European-Finnish (FIN) AF: 0.742 AC: 39587 AN: 53386

Middle Eastern (MID) AF: 0.738 AC: 4222 AN: 5720

European-Non Finnish (NFE) AF: 0.771 AC: 856526 AN: 1111576

Other (OTH) AF: 0.750 AC: 45243 AN: 60358

GnomAD4 genome AF: 0.683 AC: 103834 AN: 152042 Hom.: 36747 Cov.: 31 AF XY: 0.685 AC XY: 50892 AN XY: 74330

African (AFR) AF: 0.481 AC: 19930 AN: 41422

American (AMR) AF: 0.734 AC: 11223 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2830 AN: 3472

East Asian (EAS) AF: 0.642 AC: 3316 AN: 5164

South Asian (SAS) AF: 0.803 AC: 3863 AN: 4808

European-Finnish (FIN) AF: 0.752 AC: 7952 AN: 10568

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.770 AC: 52397 AN: 68006

Other (OTH) AF: 0.702 AC: 1484 AN: 2114

Alfa AF: 0.735 Hom.: 7434

Bravo AF: 0.672

Asia WGS AF: 0.714 AC: 2485 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Marfan syndrome (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.36
PhyloP100		0.54
Mutation Taster		=100/0	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: rs363832; hg19: chr15-48720526; COSMIC: COSV57330839; COSMIC: COSV57330839;