dbSNP rs12975322: FBN3:p.Val1326Phe (chr19-8111756-C-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.3976G>T(p.Val1326Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V1326I) has been classified as Benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.85

Publications

28 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.3976G>T	p.Val1326Phe	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>T	p.Val1326Phe	missense_variant	Exon 32 of 64	1	NM_032447.5	ENSP00000470498.1		Q75N90

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250556

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461238

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111568

Other (OTH)

AF:

0.00

AC:

AN:

60360

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.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

5.2

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.82

.;.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.68

N;N;N

PhyloP100

-1.8

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

.;N;.

REVEL

Uncertain

0.34

Sift

Benign

0.23

.;T;.

Sift4G

Uncertain

0.037

D;D;D

Polyphen

0.91

P;P;P

Vest4

0.29

MutPred

0.42

Gain of disorder (P = 0.2215);Gain of disorder (P = 0.2215);Gain of disorder (P = 0.2215);

MVP

0.75

MPC

0.54

ClinPred

0.29

GERP RS

1.7

Varity_R

0.096

gMVP

0.32

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.44

Position offset: -9

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