chr15-48639254-T-C

Variant names:

• chr15-48639254-T-C
• rs2247876
• NM_000138.5:c.164+5352A>G

Variant summary

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

The NM_000138.5(FBN1):​c.164+5352A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 152,066 control chromosomes in the GnomAD database, including 12,053 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 0.36 (12053 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00900
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.628 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.164+5352A>G		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.164+5352A>G		intron	N/A	NP_001393645.1	P35555
	FBN1	NM_001406717.1		c.164+5352A>G		intron	N/A	NP_001393646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.164+5352A>G		intron	N/A	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.164+5352A>G		intron	N/A	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.164+5352A>G		intron	N/A	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54394 AN: 151948 Hom.: 12018 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.323

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

GnomAD4 genome AF: 0.358 AC: 54484 AN: 152066 Hom.: 12053 Cov.: 32 AF XY: 0.353 AC XY: 26233 AN XY: 74334

African (AFR) AF: 0.635 AC: 26316 AN: 41466

American (AMR) AF: 0.266 AC: 4060 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 693 AN: 3472

East Asian (EAS) AF: 0.162 AC: 840 AN: 5176

South Asian (SAS) AF: 0.265 AC: 1275 AN: 4820

European-Finnish (FIN) AF: 0.270 AC: 2855 AN: 10566

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17309 AN: 67976

Other (OTH) AF: 0.322 AC: 680 AN: 2110

Alfa AF: 0.275 Hom.: 7361

Bravo AF: 0.368

Asia WGS AF: 0.266 AC: 925 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.68
DANN	Benign	0.34
PhyloP100		0.0090
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: rs2247876; hg19: chr15-48931451;