rs668842

Variant names:

• chr15-48599768-C-T
• rs668842
• NM_000138.5:c.442+371G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000138.5(FBN1):​c.442+371G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 151,922 control chromosomes in the GnomAD database, including 21,351 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (21351 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 8 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):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.442+371G>A		intron_variant	Intron 5 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.442+371G>A		intron_variant	Intron 4 of 64		NP_001393645.1
FBN1	NM_001406717.1	c.442+371G>A		intron_variant	Intron 5 of 8		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.442+371G>A		intron_variant	Intron 5 of 65	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.442+371G>A		intron_variant	Intron 5 of 66	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.442+371G>A		intron_variant	Intron 5 of 30	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.442+371G>A		intron_variant	Intron 5 of 67			ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72291 AN: 151804 Hom.: 21292 Cov.: 32

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.433

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.477 AC: 72416 AN: 151922 Hom.: 21351 Cov.: 32 AF XY: 0.473 AC XY: 35152 AN XY: 74252

African (AFR) AF: 0.841 AC: 34856 AN: 41426

American (AMR) AF: 0.390 AC: 5947 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 884 AN: 3464

East Asian (EAS) AF: 0.567 AC: 2919 AN: 5152

South Asian (SAS) AF: 0.369 AC: 1774 AN: 4810

European-Finnish (FIN) AF: 0.344 AC: 3629 AN: 10554

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20949 AN: 67946

Other (OTH) AF: 0.438 AC: 924 AN: 2112

Alfa AF: 0.356 Hom.: 46418

Bravo AF: 0.495

Asia WGS AF: 0.557 AC: 1934 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.38
DANN	Benign	0.43
PhyloP100		-1.2
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: rs668842; hg19: chr15-48891965;