rs200125037

chr15-48487150-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM1 PP2 BP4 BP6 BS1 BS2

The NM_000138.5(FBN1):c.3514G>A(p.Val1172Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000396 in 1,614,134 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1172V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 3.91

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 -7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000138.5
• PP2: Missense variant where missense usually causes diseases, FBN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.39144427).
• BP6: Variant 15-48487150-C-T is Benign according to our data. Variant chr15-48487150-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42338.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3, Benign=1}. Variant chr15-48487150-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000267 (39/1461890) while in subpopulation AFR AF= 0.000926 (31/33480). AF 95% confidence interval is 0.00067. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.3514G>A	p.Val1172Met	missense_variant	29/66	ENST00000316623.10
FBN1	NM_001406716.1	c.3514G>A	p.Val1172Met	missense_variant	28/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.3514G>A	p.Val1172Met	missense_variant	29/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251448 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135892

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727248

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74428

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2023	Variant summary: FBN1 c.3514G>A (p.Val1172Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251448 control chromosomes, predominantly at a frequency of 0.00086 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3514G>A has been reported in the literature in individuals affected with Marfan Syndrome, without strong evidence for causality (eg. Lerner-Ellis_2014). This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24793577, 33448881). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: three submitters classified the variant as VUS while three classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 19, 2019	The FBN1 c.3514G>A; p.Val1172Met variant (rs200125037) is reported in the literature in an individual affected with a suspected aortopathy (Lerner-Ellis 2014). However, the affected individual with this variant was also reported to carry a different pathogenic FBN1 variant (Lerner-Ellis 2014). The p.Val1172Met variant is found in the African population with an overall allele frequency of 0.06% (16/24964 alleles) in the Genome Aggregation Database. The valine at codon 1172 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Val1172Met variant is uncertain at this time. References: Lerner-Ellis JP et al. The spectrum of FBN1, TGFßR1, TGFßR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). Mol Genet Metab. 2014 Jun;112(2):171-6. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); Identified in a patient with features of Marfan syndrome in published literature (Lerner-Ellis et al., 2014); however, this individual also harbored a second pathogenic variant in the FBN1 gene but phase was not specified; This variant is associated with the following publications: (PMID: 12938084, 24793577) -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 21, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 23, 2023

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Benign	0.050
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.40
Sift	Benign	0.045	D
Sift4G	Benign	0.19	T
Vest4		0.58
MVP		0.59
MPC		1.3
ClinPred		0.13	T
GERP RS		4.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs200125037; hg19: chr15-48779347; COSMIC: COSV57310553;