rs11853943

Variant names:

• chr15-48487205-C-T
• rs11853943
• NM_000138.5:c.3464-5G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-48487205-C-T
• chr15-48487205-C-G

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.3464-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,816 control chromosomes in the GnomAD database, including 21,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2182 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19625 hom.)
• Consequence: FBN1 NM_000138.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002306
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.123
• Publications: 20 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=-0.8).
• BP6: Variant 15-48487205-C-T is Benign according to our data. Variant chr15-48487205-C-T is described in ClinVar as Benign. ClinVar VariationId is 137305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.342 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.3464-5G>A		splice_region intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.3464-5G>A		splice_region 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.3464-5G>A		splice_region intron	N/A	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.3464-5G>A		splice_region intron	N/A	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.637-12555G>A		intron	N/A	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25016 AN: 151904 Hom.: 2174 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.169 AC: 42392 AN: 251352 AF XY: 0.164

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.0574

Gnomad EAS exome AF: 0.342

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.155 AC: 226352 AN: 1461794 Hom.: 19625 Cov.: 33 AF XY: 0.154 AC XY: 111822 AN XY: 727200

African (AFR) AF: 0.168 AC: 5613 AN: 33480

American (AMR) AF: 0.190 AC: 8483 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1640 AN: 26136

East Asian (EAS) AF: 0.396 AC: 15699 AN: 39692

South Asian (SAS) AF: 0.131 AC: 11305 AN: 86250

European-Finnish (FIN) AF: 0.209 AC: 11153 AN: 53406

Middle Eastern (MID) AF: 0.0938 AC: 541 AN: 5768

European-Non Finnish (NFE) AF: 0.146 AC: 162494 AN: 1111948

Other (OTH) AF: 0.156 AC: 9424 AN: 60392

GnomAD4 genome AF: 0.165 AC: 25058 AN: 152022 Hom.: 2182 Cov.: 32 AF XY: 0.169 AC XY: 12545 AN XY: 74312

African (AFR) AF: 0.169 AC: 6992 AN: 41448

American (AMR) AF: 0.176 AC: 2693 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.356 AC: 1830 AN: 5144

South Asian (SAS) AF: 0.151 AC: 729 AN: 4812

European-Finnish (FIN) AF: 0.206 AC: 2174 AN: 10578

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9842 AN: 67988

Other (OTH) AF: 0.156 AC: 328 AN: 2098

Alfa AF: 0.144 Hom.: 2923

Bravo AF: 0.165

Asia WGS AF: 0.244 AC: 848 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.128

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	2	Marfan syndrome (2)
-	-	2	not provided (2)
-	-	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	-0.80
CADD	Benign	1.5
DANN	Benign	0.74
PhyloP100		-0.12
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs11853943; hg19: chr15-48779402; COSMIC: COSV57314732;