rs777826174

Variant names:

• chr15-48600231-T-C
• rs777826174
• NM_000138.5:c.350A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_000138.5(FBN1):​c.350A>G​(p.Gln117Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,612,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q117H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.67
• 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):

• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000138.5
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Weill-Marchesani syndrome 2, dominant, Acromicric dysplasia, isolated ectopia lentis, progeroid and marfanoid aspect-lipodystrophy syndrome, Marfan syndrome, stiff skin syndrome, Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection, ectopia lentis 1, isolated, autosomal dominant, Weill-Marchesani syndrome, neonatal Marfan syndrome, geleophysic dysplasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.350A>G	p.Gln117Arg	missense	Exon 5 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.350A>G	p.Gln117Arg	missense	Exon 4 of 65	NP_001393645.1	P35555
	FBN1	NM_001406717.1		c.350A>G	p.Gln117Arg	missense	Exon 5 of 9	NP_001393646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.350A>G	p.Gln117Arg	missense	Exon 5 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.350A>G		non_coding_transcript_exon	Exon 5 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.350A>G		non_coding_transcript_exon	Exon 5 of 31	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250556 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000377 AC: 55 AN: 1460594 Hom.: 0 Cov.: 30 AF XY: 0.0000372 AC XY: 27 AN XY: 726718

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1110978

Other (OTH) AF: 0.0000331 AC: 2 AN: 60352

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000580 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Familial thoracic aortic aneurysm and aortic dissection (2)
-	1	-	Marfan syndrome (1)
-	1	-	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.094	D
PhyloP100		7.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.37
Sift	Benign	0.058	T
Sift4G	Benign	0.14	T
Vest4		0.88
MVP		0.91
MPC		1.5
ClinPred		0.57	D
GERP RS		6.2
Mutation Taster		=50/50

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: rs777826174; hg19: chr15-48892428;