chr19-8085509-C-T

Position:

chr19-8085509-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.6941G>A(p.Ser2314Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,594,920 control chromosomes in the GnomAD database, including 2,297 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 0.068 ( 1227 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 1070 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.977

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=0.0036964118).

BP6

Variant 19-8085509-C-T is Benign according to our data. Variant chr19-8085509-C-T is described in ClinVar as [Benign]. Clinvar id is 1601594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 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.6941G>A	p.Ser2314Asn	missense_variant	56/64	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.6941G>A	p.Ser2314Asn	missense_variant	56/64	1	NM_032447.5	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6 linkuse as main transcript	c.6941G>A	p.Ser2314Asn	missense_variant	55/63	1		ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5 linkuse as main transcript	c.6941G>A	p.Ser2314Asn	missense_variant	56/64	1		ENSP00000472324.1	Q75N90
FBN3	ENST00000651877.1 linkuse as main transcript	c.7067G>A	p.Ser2356Asn	missense_variant	56/64			ENSP00000498507.1	A0A494C0D8

Frequencies

GnomAD3 genomes

AF:

0.0683

AC:

10388

AN:

152128

Hom.:

1223

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.0611

GnomAD3 exomes

AF:

0.0176

AC:

3779

AN:

215246

Hom.:

358

AF XY:

0.0131

AC XY:

1534

AN XY:

117120

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000800

Gnomad OTH exome

AF:

0.00897

GnomAD4 exome

AF:

0.00753

AC:

10870

AN:

1442674

Hom.:

1070

Cov.:

AF XY:

0.00662

AC XY:

4739

AN XY:

715990

show subpopulations

Gnomad4 AFR exome

AF:

0.247

Gnomad4 AMR exome

AF:

0.0136

Gnomad4 ASJ exome

AF:

0.0179

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00226

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000381

Gnomad4 OTH exome

AF:

0.0167

GnomAD4 genome

AF:

0.0684

AC:

10419

AN:

152246

Hom.:

1227

Cov.:

AF XY:

0.0666

AC XY:

4958

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.236

Gnomad4 AMR

AF:

0.0230

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.0605

Alfa

AF:

0.0146

Hom.:

343

Bravo

AF:

0.0780

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.227

AC:

998

ESP6500EA

AF:

0.00222

AC:

ExAC

AF:

0.0203

AC:

2449

Asia WGS

AF:

0.0150

AC:

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	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

Apr 04, 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

0.14

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

T;T;T

Eigen

Benign

0.11

Eigen_PC

Benign

-0.036

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.41

.;.;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.3

MutationAssessor

Uncertain

2.5

M;M;M

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.8

.;N;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.018

.;D;.

Sift4G

Uncertain

0.029

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.31

MPC

0.59

ClinPred

0.012

GERP RS

2.3

Varity_R

0.43

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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