Genetic Variant NM_032447.5:c.3877A>C (chr19-8112061-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032447.5(FBN3):c.3877A>C(p.Ser1293Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1293G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 28)

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.390

Publications

20 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1276069).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032447.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	NM_032447.5	MANE Select	c.3877A>C	p.Ser1293Arg	missense	Exon 31 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.3877A>C	p.Ser1293Arg	missense	Exon 31 of 64	NP_001308360.1	Q75N90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBN3	ENST00000600128.6	TSL:1 MANE Select	c.3877A>C	p.Ser1293Arg	missense	Exon 31 of 64	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6	TSL:1	c.3877A>C	p.Ser1293Arg	missense	Exon 30 of 63	ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5	TSL:1	c.3877A>C	p.Ser1293Arg	missense	Exon 31 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73792

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41034

American (AMR)

AF:

0.00

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67864

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

14998

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.4

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.041

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.57

M_CAP

Benign

0.034

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.1

PhyloP100

-0.39

PrimateAI

Benign

0.30

PROVEAN

Benign

0.35

REVEL

Benign

0.16

Sift

Benign

0.56

Sift4G

Benign

0.53

Polyphen

0.0030

Vest4

0.33

MutPred

0.40

Loss of disorder (P = 0.1066)

MVP

0.48

MPC

0.22

ClinPred

0.030

GERP RS

-5.6

Varity_R

0.025

gMVP

0.42

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over