rs794728218

Positions:

• chr15-48474319-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000138.5(FBN1):​c.4146T>A​(p.Asn1382Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. N1382I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.00500

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 15-48474319-A-T is Pathogenic according to our data. Variant chr15-48474319-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200037.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr15-48474319-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4146T>A	p.Asn1382Lys	missense_variant	34/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4146T>A	p.Asn1382Lys	missense_variant	33/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4146T>A	p.Asn1382Lys	missense_variant	34/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2016	Variant summary: The FBN1 c.4146T>A (p.Asn1382Lys) is located in calcium binding EGF-like domain 18 of the protein and 4/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 121088 control chromosomes from ExAC. In literature, this variant is reported as a 'mutation' found in one patient with Marfan or Marfan-like syndrome (Howarth_2007). Mutations at the same residue, N1382I and N1382S have also been reported in association with MFS (PMIDs 7611299 and 18087243), suggesting that the codon is mutational hot-spot. In addition, mutations in nearby residues (C1374G, C1374S, C1374Y, C1380Y, K1381N, M1384L, Y1387C, C1389R, C1391F, etc.) have been reported in association with Marfan syndrome or other FBN1-related disorder (HGMD), further supporting the functional importance of this region of the protein. One clinical laboratory in ClinVar has classified this variant as pathogenic and reports the variant in TAAD panel. Taken together, this variant is currently classified as VUS-possibly pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2017	The N1382K likely pathogenic variant in the FBN1 gene has been reported in association in one of 262 unrelated individuals with Marfan syndrome or Marfan-like phenotype tested at a national health service laboratory; however, no detailed clinical information or segregation data were provided (Howarth et al., 2007). Additionally, the N1382K protein substitution caused by a different nucleotide substitution (c.4146 T>G) has been identified in an unrelated individual referred for TAAD / Marfan Syndrome / Related Disorders genetic testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N1382K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a calcium-binding residue that is conserved across species, within the calcium-binding EGF-like 23 domain. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Benign	0.69
Eigen	Benign	0.068
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.95
MutPred		0.97		Gain of methylation at N1382 (P = 0.0197);
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		-5.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728218; hg19: chr15-48766516;