chr15-48613072-C-T

Position:

• chr15-48613072-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1 PM5 PP2 BP6 BS2

The ENST00000316623.10(FBN1):​c.185G>A​(p.Arg62His) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R62C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: FBN1 ENST00000316623.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: 3.67

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000316623.10
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48613073-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
• BP6: Variant 15-48613072-C-T is Benign according to our data. Variant chr15-48613072-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42296.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2}. Variant chr15-48613072-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.185G>A	p.Arg62His	missense_variant	3/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.185G>A	p.Arg62His	missense_variant	2/65		NP_001393645.1
FBN1	NM_001406717.1	c.185G>A	p.Arg62His	missense_variant	3/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.185G>A	p.Arg62His	missense_variant	3/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.185G>A	p.Arg62His	missense_variant, NMD_transcript_variant	3/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.185G>A	p.Arg62His	missense_variant, NMD_transcript_variant	3/68			ENSP00000501333
FBN1	ENST00000537463.6	c.185G>A	p.Arg62His	missense_variant, NMD_transcript_variant	3/31	5		ENSP00000440294

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000561 AC: 14 AN: 249372 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135244

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.0000580

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: 0.0000623

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1461028 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 726800

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74280

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Marfan syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 30, 2024	This missense variant replaces arginine with histidine at codon 62 of the FBN1 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 26621581, 29357934 ) as well as in one healthy individual (PMID: 28659821). This variant has been identified in 15/280762 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2024	Has been previously observed in individuals referred for Marfan or Marfan-like syndromes and in a patient with tricuspid aortic valve (PMID: 24793577, 26621581, 29357934); Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24793577, 22102435, 26621581, 12938084, 29357934, 37937776, 28659821) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Arg62His variant in FBN1 has been identified in 1 individual with features of Marfan syndrome and 2 individuals with aortic aneurysm or dissection (Regalado 2016, Becerra-Muñoz 2018, LMM data). It has also been identified in 0.016% (4/24662) of African chromosomes by Genome Aggregation Databse (http://gnomad.broadinstitute.org). Arginine (Arg) at position 62 is not conserved in mammals or evolutionarily distant species and 6 mammals (marmoset, prairie vole, naked mole rat, guinea pig, chinchilla, brush tailed rat) carry a Histidine (His) at this position despite high nearby amino acid conservation, suggesting that this change may be tolerated. In summary, while the clinical significance of the p.Arg62His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4_Strong, PS4_Supporting. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2023	Variant summary: FBN1 c.185G>A (p.Arg62His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249738 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FBN1 causing Marfan Syndrome (6e-05 vs 0.00011), allowing no conclusion about variant significance. c.185G>A has been reported in the literature in individuals affected with Marfan Syndrome (Lerner-Ellis_2014), isolated Thoracic Aneurism (Becerra-Munoz_2018; Regalado_2016) as well as in healthy individual without any cardiac abnormalities (Gillis_2017). These data do not allow any conclusion about variant significance. 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, 26621581, 29357934, 28659821). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7), likely benign (n=1), or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2023	This missense variant replaces arginine with histidine at codon 62 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 26621581, 29357934 ) and in a healthy individual as well (PMID: 28659821). This variant has been identified in 15/280762 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2024	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. -

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jan 20, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.45	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0020	D
Vest4		0.27
MVP		0.77
MPC		1.6
ClinPred		0.72	D
GERP RS		3.3

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: rs145942328; hg19: chr15-48905269; COSMIC: COSV57319852;