rs371929738

chr15-48516268-A-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000138.5(FBN1):c.1242T>G(p.Pro414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000064 in 1,578,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: FBN1 NM_000138.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.380

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-48516268-A-C is Benign according to our data. Variant chr15-48516268-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 514299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.38 with no splicing effect.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1242T>G	p.Pro414=	synonymous_variant	11/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1242T>G	p.Pro414=	synonymous_variant	10/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1242T>G	p.Pro414=	synonymous_variant	11/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.1242T>G	p.Pro414=	synonymous_variant, NMD_transcript_variant	11/67	1
FBN1	ENST00000674301.2	c.1242T>G	p.Pro414=	synonymous_variant, NMD_transcript_variant	11/68
FBN1	ENST00000537463.6	c.636+21443T>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000465 AC: 7 AN: 150468 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251290 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000658 AC: 94 AN: 1427568 Hom.: 0 Cov.: 33 AF XY: 0.0000592 AC XY: 42 AN XY: 709980

Gnomad4 AFR exome AF: 0.0000618

Gnomad4 AMR exome AF: 0.000206

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000744

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome AF: 0.0000465 AC: 7 AN: 150596 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73630

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000592

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2016	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 17, 2022	- -

Marfan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2020

- -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	4.1
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs371929738; hg19: chr15-48808465;