chr15-48468553-T-C

Variant names:

• chr15-48468553-T-C
• rs55840194
• NM_000138.5:c.4460-19A>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.4460-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,613,552 control chromosomes in the GnomAD database, including 599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (55 hom., cov: 32)
  • Exomes 𝑓: 0.015 (544 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.458
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-48468553-T-C is Benign according to our data. Variant chr15-48468553-T-C is described in ClinVar as Benign. ClinVar VariationId is 137308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0773 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.4460-19A>G		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.4460-19A>G		intron	N/A	NP_001393645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.4460-19A>G		intron	N/A	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.4460-19A>G		intron	N/A	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.*223-19A>G		intron	N/A	ENSP00000440294.2

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2673 AN: 151984 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.0316

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.0836

Gnomad SAS AF: 0.0473

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.0212

GnomAD2 exomes AF: 0.0248 AC: 6222 AN: 250842 AF XY: 0.0238

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0511

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0763

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.0244

GnomAD4 exome AF: 0.0153 AC: 22358 AN: 1461450 Hom.: 544 Cov.: 32 AF XY: 0.0158 AC XY: 11452 AN XY: 727034

African (AFR) AF: 0.0135 AC: 452 AN: 33478

American (AMR) AF: 0.0505 AC: 2260 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 309 AN: 26132

East Asian (EAS) AF: 0.110 AC: 4365 AN: 39674

South Asian (SAS) AF: 0.0354 AC: 3051 AN: 86248

European-Finnish (FIN) AF: 0.0117 AC: 625 AN: 53324

Middle Eastern (MID) AF: 0.0243 AC: 140 AN: 5764

European-Non Finnish (NFE) AF: 0.00899 AC: 9995 AN: 1111748

Other (OTH) AF: 0.0192 AC: 1161 AN: 60370

GnomAD4 genome AF: 0.0176 AC: 2679 AN: 152102 Hom.: 55 Cov.: 32 AF XY: 0.0191 AC XY: 1420 AN XY: 74328

African (AFR) AF: 0.0136 AC: 566 AN: 41480

American (AMR) AF: 0.0318 AC: 486 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.0838 AC: 433 AN: 5168

South Asian (SAS) AF: 0.0478 AC: 230 AN: 4816

European-Finnish (FIN) AF: 0.0144 AC: 152 AN: 10586

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00957 AC: 651 AN: 68016

Other (OTH) AF: 0.0209 AC: 44 AN: 2102

Alfa AF: 0.0139 Hom.: 11

Bravo AF: 0.0193

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	-0.84
CADD	Benign	2.0
DANN	Benign	0.27
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55840194; hg19: chr15-48760750; COSMIC: COSV107345538; COSMIC: COSV107345538;