rs33967815

Positions:

chr19-8103661-C-T

Variant summary

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

The NM_032447.5(FBN3):c.4840G>A(p.Gly1614Ser) variant causes a missense change. The variant allele was found at a frequency of 0.287 in 1,612,494 control chromosomes in the GnomAD database, including 72,056 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 0.23 ( 4893 hom., cov: 31)

Exomes 𝑓: 0.29 ( 67163 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.59

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=0.0020065904).

BP6

Variant 19-8103661-C-T is Benign according to our data. Variant chr19-8103661-C-T is described in ClinVar as [Benign]. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8103661-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 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.4840G>A	p.Gly1614Ser	missense_variant	39/64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FBN3	ENST00000600128.6 linkuse as main transcript	c.4840G>A	p.Gly1614Ser	missense_variant	39/64	1	NM_032447.5	ENSP00000470498
FBN3	ENST00000270509.6 linkuse as main transcript	c.4840G>A	p.Gly1614Ser	missense_variant	38/63	1		ENSP00000270509
FBN3	ENST00000601739.5 linkuse as main transcript	c.4840G>A	p.Gly1614Ser	missense_variant	39/64	1		ENSP00000472324
FBN3	ENST00000651877.1 linkuse as main transcript	c.4966G>A	p.Gly1656Ser	missense_variant	39/64			ENSP00000498507	P1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34488

AN:

151834

Hom.:

4897

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0810

Gnomad AMI

AF:

0.296

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.353

Gnomad EAS

AF:

0.0556

Gnomad SAS

AF:

0.180

Gnomad FIN

AF:

0.246

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.326

Gnomad OTH

AF:

0.262

GnomAD3 exomes

AF:

0.244

AC:

61177

AN:

251112

Hom.:

8794

AF XY:

0.251

AC XY:

34067

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.0778

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.0561

Gnomad SAS exome

AF:

0.195

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.330

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.293

AC:

428578

AN:

1460542

Hom.:

67163

Cov.:

AF XY:

0.292

AC XY:

212467

AN XY:

726626

show subpopulations

Gnomad4 AFR exome

AF:

0.0749

Gnomad4 AMR exome

AF:

0.152

Gnomad4 ASJ exome

AF:

0.338

Gnomad4 EAS exome

AF:

0.0568

Gnomad4 SAS exome

AF:

0.195

Gnomad4 FIN exome

AF:

0.255

Gnomad4 NFE exome

AF:

0.323

Gnomad4 OTH exome

AF:

0.281

GnomAD4 genome

AF:

0.227

AC:

34478

AN:

151952

Hom.:

4893

Cov.:

AF XY:

0.221

AC XY:

16437

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.0809

Gnomad4 AMR

AF:

0.202

Gnomad4 ASJ

AF:

0.353

Gnomad4 EAS

AF:

0.0555

Gnomad4 SAS

AF:

0.179

Gnomad4 FIN

AF:

0.246

Gnomad4 NFE

AF:

0.326

Gnomad4 OTH

AF:

0.262

Alfa

AF:

0.300

Hom.:

12784

Bravo

AF:

0.218

TwinsUK

AF:

0.320

AC:

1185

ALSPAC

AF:

0.318

AC:

1227

ESP6500AA

AF:

0.0856

AC:

377

ESP6500EA

AF:

0.337

AC:

2900

ExAC

AF:

0.247

AC:

29969

Asia WGS

AF:

0.126

AC:

437

AN:

3478

EpiCase

AF:

0.338

EpiControl

AF:

0.336

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

FBN3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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

0.070

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

.;.;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.68

N;N;N

MutationTaster

Benign

0.000021

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.4

.;D;.

REVEL

Uncertain

0.55

Sift

Uncertain

0.024

.;D;.

Sift4G

Uncertain

0.049

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.37

MPC

0.65

ClinPred

0.019

GERP RS

3.6

Varity_R

0.49

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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