rs140587

Variant names:

• chr15-48488156-G-A
• rs140587
• NM_000138.5:c.3294C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-48488156-G-A
• chr15-48488156-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000138.5(FBN1):​c.3294C>T​(p.Asp1098Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 1,614,056 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (104 hom.)
• Consequence: FBN1 NM_000138.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: -0.813
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-48488156-G-A is Benign according to our data. Variant chr15-48488156-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.813 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00734 (1117/152194) while in subpopulation NFE AF = 0.00873 (594/68010). AF 95% confidence interval is 0.00815. There are 7 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,Unknown,AR gene

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.3294C>T	p.Asp1098Asp	synonymous	Exon 27 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.3294C>T	p.Asp1098Asp	synonymous	Exon 26 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.3294C>T	p.Asp1098Asp	synonymous	Exon 27 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.3294C>T		non_coding_transcript_exon	Exon 27 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.3294C>T		non_coding_transcript_exon	Exon 27 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1117 AN: 152078 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00873

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00773 AC: 1944 AN: 251468 AF XY: 0.00748

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.00882

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00819 AC: 11979 AN: 1461862 Hom.: 104 Cov.: 32 AF XY: 0.00789 AC XY: 5741 AN XY: 727240

African (AFR) AF: 0.00140 AC: 47 AN: 33478

American (AMR) AF: 0.00172 AC: 77 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.0377 AC: 2014 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00846 AC: 9412 AN: 1111982

Other (OTH) AF: 0.00636 AC: 384 AN: 60396

GnomAD4 genome AF: 0.00734 AC: 1117 AN: 152194 Hom.: 7 Cov.: 32 AF XY: 0.00825 AC XY: 614 AN XY: 74408

African (AFR) AF: 0.00144 AC: 60 AN: 41532

American (AMR) AF: 0.00105 AC: 16 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0377 AC: 399 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00873 AC: 594 AN: 68010

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00726 Hom.: 1

Bravo AF: 0.00485

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00563

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	3	Marfan syndrome (3)
-	-	1	Acromicric dysplasia (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Ectopia lentis 1, isolated, autosomal dominant (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
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.26
DANN	Benign	0.37
PhyloP100		-0.81
Mutation Taster		=99/1	polymorphism

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: rs140587; hg19: chr15-48780353;