Genetic Variant FBN1:p.Ile329Thr (chr15-48526132-A-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000138.5(FBN1):c.986T>C(p.Ile329Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,086 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I329V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0068 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 16 hom. )

Consequence

FBN1
NM_000138.5 missense, splice_region

Scores

Splicing: ADA: 0.7362

Clinical Significance

Benign reviewed by expert panel U:1B:21

Conservation

PhyloP100: 7.52

Publications

11 publications found

Variant links:

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

FBN1 links:

LOC124903488 (HGNC:):

LOC124903488 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 4 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 Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0101932585).

BP6

Variant 15-48526132-A-G is Benign according to our data. Variant chr15-48526132-A-G is described in ClinVar as Benign. ClinVar VariationId is 36133.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00676 (1030/152278) while in subpopulation AFR AF = 0.0236 (982/41552). AF 95% confidence interval is 0.0224. There are 17 homozygotes in GnomAd4. There are 481 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AD,AR,Unknown gene

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.986T>C	p.Ile329Thr	missense splice_region	Exon 9 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.986T>C	p.Ile329Thr	missense splice_region	Exon 8 of 65	NP_001393645.1	P35555

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBN1	ENST00000316623.10	TSL:1 MANE Select	c.986T>C	p.Ile329Thr	missense splice_region	Exon 9 of 66	ENSP00000325527.5	P35555
FBN1	ENST00000559133.6	TSL:1	n.986T>C		splice_region non_coding_transcript_exon	Exon 9 of 67	ENSP00000453958.2	H0YND0
FBN1	ENST00000674301.2		n.986T>C		splice_region non_coding_transcript_exon	Exon 9 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes

AF:

0.00674

AC:

1025

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

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:

0.00526

GnomAD2 exomes

AF:

0.00163

AC:

410

AN:

251412

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.0234

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000659

AC:

964

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

371

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0245

AC:

821

AN:

33478

American (AMR)

AF:

0.000760

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111964

Other (OTH)

AF:

0.00149

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00676

AC:

1030

AN:

152278

Hom.:

Cov.:

AF XY:

0.00646

AC XY:

481

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0236

AC:

982

AN:

41552

American (AMR)

AF:

0.00216

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68018

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

139

186

232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00253

Hom.:

Bravo

AF:

0.00766

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00229

AC:

278

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Marfan syndrome (7)

Familial thoracic aortic aneurysm and aortic dissection (4)

not provided (2)

not specified (2)

Acromicric dysplasia (1)

Connective tissue disorder (1)

Ectopia lentis 1, isolated, autosomal dominant (1)

Geleophysic dysplasia (1)

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

Stiff skin syndrome (1)

Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.012

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.19

PhyloP100

7.5

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.47

Sift

Uncertain

0.025

Sift4G

Benign

0.094

Vest4

0.77

MVP

0.49

MPC

0.69

ClinPred

0.068

GERP RS

6.0

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.74

dbscSNV1_RF

Benign

0.58

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over