dbSNP rs7245429: FBN3:p.Pro1958Leu (chr19-8094478-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032447.5(FBN3):c.5873C>T(p.Pro1958Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 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. P1958H) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.29

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.5873C>T	p.Pro1958Leu	missense_variant	Exon 47 of 64	ENST00000600128.6	NP_115823.3	Q75N90A8KAY2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN3	ENST00000600128.6 link	c.5873C>T	p.Pro1958Leu	missense_variant	Exon 47 of 64	1	NM_032447.5	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6 link	c.5873C>T	p.Pro1958Leu	missense_variant	Exon 46 of 63	1		ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5 link	c.5873C>T	p.Pro1958Leu	missense_variant	Exon 47 of 64	1		ENSP00000472324.1	Q75N90
FBN3	ENST00000651877.1 link	c.5999C>T	p.Pro2000Leu	missense_variant	Exon 47 of 64			ENSP00000498507.1	A0A494C0D8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460952

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111448

Other (OTH)

AF:

0.00

AC:

AN:

60350

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

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.36

T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

.;.;T

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Uncertain

-0.0075

MutationAssessor

Benign

2.0

M;M;M

PhyloP100

5.3

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-6.6

.;D;.

REVEL

Benign

0.29

Sift

Benign

0.091

.;T;.

Sift4G

Benign

0.13

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.27

MutPred

0.59

Gain of stability (P = 0.0227);Gain of stability (P = 0.0227);Gain of stability (P = 0.0227);

MVP

0.76

MPC

0.24

ClinPred

0.43

GERP RS

1.4

Varity_R

0.14

gMVP

0.74

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over