19-8118987-G-A

Position:

chr19-8118987-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032447.5(FBN3):c.3247C>T(p.Arg1083Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,609,962 control chromosomes in the GnomAD database, including 3,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.049 ( 375 hom., cov: 32)

Exomes 𝑓: 0.048 ( 2936 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.94

Variant links:

Genes affected

FBN3 (HGNC:18794): (fibrillin 3) This gene encodes a memebr of the fibrillin protein family. Fibrillins are extracellular matrix molecules that assemble into microfibrils in many connective tissues. This gene is most highly expressed in fetal tissues and its protein product is localized to extracellular microfibrils of developing skeletal elements, skin, lung, kidney, and skeletal muscle. This gene is potentially involved in Weill-Marchesani syndrome. [provided by RefSeq, Mar 2016]

FBN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031781197).

BP6

Variant 19-8118987-G-A is Benign according to our data. Variant chr19-8118987-G-A is described in ClinVar as [Benign]. Clinvar id is 1540834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5 linkuse as main transcript	c.3247C>T	p.Arg1083Trp	missense_variant	26/64	ENST00000600128.6	NP_115823.3	Q75N90A8KAY2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FBN3	ENST00000600128.6 linkuse as main transcript	c.3247C>T	p.Arg1083Trp	missense_variant	26/64	1	NM_032447.5	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6 linkuse as main transcript	c.3247C>T	p.Arg1083Trp	missense_variant	25/63	1		ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5 linkuse as main transcript	c.3247C>T	p.Arg1083Trp	missense_variant	26/64	1		ENSP00000472324.1	Q75N90
FBN3	ENST00000651877.1 linkuse as main transcript	c.3373C>T	p.Arg1125Trp	missense_variant	26/64			ENSP00000498507.1	A0A494C0D8

Frequencies

GnomAD3 genomes

AF:

0.0494

AC:

7519

AN:

152160

Hom.:

371

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.0279

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.0416

Gnomad FIN

AF:

0.0816

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0367

Gnomad OTH

AF:

0.0667

GnomAD3 exomes

AF:

0.0713

AC:

17874

AN:

250778

Hom.:

1177

AF XY:

0.0667

AC XY:

9045

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.0285

Gnomad EAS exome

AF:

0.184

Gnomad SAS exome

AF:

0.0446

Gnomad FIN exome

AF:

0.0786

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0687

GnomAD4 exome

AF:

0.0483

AC:

70358

AN:

1457684

Hom.:

2936

Cov.:

AF XY:

0.0479

AC XY:

34675

AN XY:

724258

show subpopulations

Gnomad4 AFR exome

AF:

0.0114

Gnomad4 AMR exome

AF:

0.190

Gnomad4 ASJ exome

AF:

0.0269

Gnomad4 EAS exome

AF:

0.206

Gnomad4 SAS exome

AF:

0.0481

Gnomad4 FIN exome

AF:

0.0738

Gnomad4 NFE exome

AF:

0.0371

Gnomad4 OTH exome

AF:

0.0521

GnomAD4 genome

AF:

0.0494

AC:

7528

AN:

152278

Hom.:

375

Cov.:

AF XY:

0.0530

AC XY:

3944

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.141

Gnomad4 ASJ

AF:

0.0279

Gnomad4 EAS

AF:

0.183

Gnomad4 SAS

AF:

0.0412

Gnomad4 FIN

AF:

0.0816

Gnomad4 NFE

AF:

0.0367

Gnomad4 OTH

AF:

0.0655

Alfa

AF:

0.0422

Hom.:

359

Bravo

AF:

0.0549

TwinsUK

AF:

0.0396

AC:

147

ALSPAC

AF:

0.0319

AC:

123

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.0387

AC:

333

ExAC

AF:

0.0632

AC:

7670

Asia WGS

AF:

0.101

AC:

350

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

FBN3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D;D

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

.;.;D

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

M;M;M

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-6.9

.;D;.

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.039

B;B;B

Vest4

0.38

MPC

0.68

ClinPred

0.086

GERP RS

0.39

Varity_R

0.80

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over