Genetic Variant FBN3:p.Val1326Ile (chr19-8111756-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_032447.5(FBN3):c.3976G>A(p.Val1326Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,612,612 control chromosomes in the GnomAD database, including 50,968 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.25 ( 4972 hom., cov: 28)

Exomes 𝑓: 0.25 ( 45996 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.85

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=1.3646483E-4).

BP6

Variant 19-8111756-C-T is Benign according to our data. Variant chr19-8111756-C-T is described in ClinVar as [Benign]. Clinvar id is 1562437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8111756-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.3976G>A	p.Val1326Ile	missense_variant	Exon 32 of 64	ENST00000600128.6	NP_115823.3	Q75N90A8KAY2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6 link	c.3976G>A	p.Val1326Ile	missense_variant	Exon 32 of 64	1	NM_032447.5	ENSP00000470498.1		Q75N90

Frequencies

GnomAD3 genomes

AF:

0.251

AC:

38087

AN:

151690

Hom.:

4946

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.325

Gnomad ASJ

AF:

0.242

Gnomad EAS

AF:

0.433

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.217

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.275

GnomAD3 exomes

AF:

0.264

AC:

66126

AN:

250556

Hom.:

9473

AF XY:

0.258

AC XY:

35029

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.240

Gnomad AMR exome

AF:

0.361

Gnomad ASJ exome

AF:

0.249

Gnomad EAS exome

AF:

0.447

Gnomad SAS exome

AF:

0.215

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.232

Gnomad OTH exome

AF:

0.253

GnomAD4 exome

AF:

0.246

AC:

358730

AN:

1460804

Hom.:

45996

Cov.:

AF XY:

0.245

AC XY:

177800

AN XY:

726638

show subpopulations

Gnomad4 AFR exome

AF:

0.235

Gnomad4 AMR exome

AF:

0.363

Gnomad4 ASJ exome

AF:

0.254

Gnomad4 EAS exome

AF:

0.470

Gnomad4 SAS exome

AF:

0.218

Gnomad4 FIN exome

AF:

0.216

Gnomad4 NFE exome

AF:

0.236

Gnomad4 OTH exome

AF:

0.252

GnomAD4 genome

AF:

0.251

AC:

38155

AN:

151808

Hom.:

4972

Cov.:

AF XY:

0.250

AC XY:

18536

AN XY:

74176

show subpopulations

Gnomad4 AFR

AF:

0.240

Gnomad4 AMR

AF:

0.327

Gnomad4 ASJ

AF:

0.242

Gnomad4 EAS

AF:

0.432

Gnomad4 SAS

AF:

0.198

Gnomad4 FIN

AF:

0.224

Gnomad4 NFE

AF:

0.237

Gnomad4 OTH

AF:

0.273

Alfa

AF:

0.239

Hom.:

11860

Bravo

AF:

0.263

TwinsUK

AF:

0.244

AC:

903

ALSPAC

AF:

0.231

AC:

890

ESP6500AA

AF:

0.256

AC:

1126

ESP6500EA

AF:

0.242

AC:

2080

ExAC

AF:

0.255

AC:

31005

Asia WGS

AF:

0.311

AC:

1083

AN:

3478

EpiCase

AF:

0.229

EpiControl

AF:

0.232

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.077

DANN

Benign

0.83

DEOGEN2

Benign

0.049

T;T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.32

.;.;T

MetaRNN

Benign

0.00014

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.35

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.040

.;N;.

REVEL

Benign

0.15

Sift

Benign

0.53

.;T;.

Sift4G

Benign

0.086

T;T;T

Polyphen

0.56

P;P;P

Vest4

0.043

MPC

0.16

ClinPred

0.0029

GERP RS

1.7

Varity_R

0.021

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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