rs7246376

Positions:

chr19-8138444-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.986C>T(p.Pro329Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,612,480 control chromosomes in the GnomAD database, including 40,854 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 ( 4531 hom., cov: 33)

Exomes 𝑓: 0.21 ( 36323 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0290

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=5.2250016E-5).

BP6

Variant 19-8138444-G-A is Benign according to our data. Variant chr19-8138444-G-A is described in ClinVar as [Benign]. Clinvar id is 1600608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8138444-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 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.986C>T	p.Pro329Leu	missense_variant	9/64	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.986C>T	p.Pro329Leu	missense_variant	9/64	1	NM_032447.5	ENSP00000470498
FBN3	ENST00000270509.6 linkuse as main transcript	c.986C>T	p.Pro329Leu	missense_variant	8/63	1		ENSP00000270509
FBN3	ENST00000601739.5 linkuse as main transcript	c.986C>T	p.Pro329Leu	missense_variant	9/64	1		ENSP00000472324
FBN3	ENST00000651877.1 linkuse as main transcript	c.1112C>T	p.Pro371Leu	missense_variant	9/64			ENSP00000498507	P1

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

34856

AN:

152090

Hom.:

4517

Cov.:

show subpopulations

Gnomad AFR

AF:

0.254

Gnomad AMI

AF:

0.333

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.287

Gnomad EAS

AF:

0.472

Gnomad SAS

AF:

0.412

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.287

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.233

GnomAD3 exomes

AF:

0.266

AC:

65459

AN:

246014

Hom.:

10371

AF XY:

0.265

AC XY:

35428

AN XY:

133708

show subpopulations

Gnomad AFR exome

AF:

0.260

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.470

Gnomad SAS exome

AF:

0.409

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.182

Gnomad OTH exome

AF:

0.238

GnomAD4 exome

AF:

0.207

AC:

302638

AN:

1460272

Hom.:

36323

Cov.:

AF XY:

0.212

AC XY:

154353

AN XY:

726414

show subpopulations

Gnomad4 AFR exome

AF:

0.257

Gnomad4 AMR exome

AF:

0.348

Gnomad4 ASJ exome

AF:

0.292

Gnomad4 EAS exome

AF:

0.444

Gnomad4 SAS exome

AF:

0.405

Gnomad4 FIN exome

AF:

0.161

Gnomad4 NFE exome

AF:

0.175

Gnomad4 OTH exome

AF:

0.224

GnomAD4 genome

AF:

0.229

AC:

34905

AN:

152208

Hom.:

4531

Cov.:

AF XY:

0.235

AC XY:

17509

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.255

Gnomad4 AMR

AF:

0.274

Gnomad4 ASJ

AF:

0.287

Gnomad4 EAS

AF:

0.472

Gnomad4 SAS

AF:

0.410

Gnomad4 FIN

AF:

0.153

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.234

Alfa

AF:

0.204

Hom.:

7199

Bravo

AF:

0.240

TwinsUK

AF:

0.173

AC:

642

ALSPAC

AF:

0.180

AC:

692

ESP6500AA

AF:

0.254

AC:

1120

ESP6500EA

AF:

0.184

AC:

1579

ExAC

AF:

0.260

AC:

31605

Asia WGS

AF:

0.454

AC:

1576

AN:

3478

EpiCase

AF:

0.191

EpiControl

AF:

0.191

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

Oct 17, 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

0.071

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.64

.;.;T

MetaRNN

Benign

0.000052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

.;N;.

REVEL

Benign

0.16

Sift

Benign

0.29

.;T;.

Sift4G

Uncertain

0.058

T;T;T

Polyphen

0.031

B;B;B

Vest4

0.063

MPC

0.20

ClinPred

0.0034

GERP RS

2.0

Varity_R

0.028

gMVP

0.46

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