15-48465935-A-C

Variant names:

• chr15-48465935-A-C
• rs55694948
• NM_000138.5:c.4748-77T>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.4748-77T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 941,574 control chromosomes in the GnomAD database, including 12,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2660 hom., cov: 32)
  • Exomes 𝑓: 0.16 (9962 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.306
• Publications: 3 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 15-48465935-A-C is Benign according to our data. Variant chr15-48465935-A-C is described in ClinVar as Benign. ClinVar VariationId is 1237499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4748-77T>G		intron_variant	Intron 38 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4748-77T>G		intron_variant	Intron 37 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4748-77T>G		intron_variant	Intron 38 of 65	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27638 AN: 152022 Hom.: 2650 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.155 AC: 122496 AN: 789434 Hom.: 9962 AF XY: 0.155 AC XY: 64595 AN XY: 415952

African (AFR) AF: 0.249 AC: 4923 AN: 19754

American (AMR) AF: 0.150 AC: 5889 AN: 39324

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4035 AN: 21698

East Asian (EAS) AF: 0.200 AC: 6873 AN: 34372

South Asian (SAS) AF: 0.171 AC: 11803 AN: 68824

European-Finnish (FIN) AF: 0.147 AC: 6951 AN: 47286

Middle Eastern (MID) AF: 0.207 AC: 922 AN: 4452

European-Non Finnish (NFE) AF: 0.145 AC: 74550 AN: 515382

Other (OTH) AF: 0.171 AC: 6550 AN: 38342

GnomAD4 genome AF: 0.182 AC: 27669 AN: 152140 Hom.: 2660 Cov.: 32 AF XY: 0.180 AC XY: 13387 AN XY: 74370

African (AFR) AF: 0.249 AC: 10320 AN: 41464

American (AMR) AF: 0.168 AC: 2573 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 608 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1035 AN: 5176

South Asian (SAS) AF: 0.172 AC: 829 AN: 4814

European-Finnish (FIN) AF: 0.135 AC: 1434 AN: 10596

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10244 AN: 67998

Other (OTH) AF: 0.196 AC: 414 AN: 2114

Alfa AF: 0.0822 Hom.: 106

Bravo AF: 0.188

Asia WGS AF: 0.239 AC: 828 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.3
DANN	Benign	0.37
PhyloP100		0.31
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: rs55694948; hg19: chr15-48758132;