Genetic Variant NM_032447.5:c.8321G>T (chr19-8066028-C-A) – 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.8321G>T(p.Arg2774Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,742 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. R2774Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.120

Publications

7 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=0.09693357).

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.8321G>T	p.Arg2774Leu	missense	Exon 64 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.8321G>T	p.Arg2774Leu	missense	Exon 64 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.8321G>T	p.Arg2774Leu	missense	Exon 64 of 64	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6	TSL:1	c.8321G>T	p.Arg2774Leu	missense	Exon 63 of 63	ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5	TSL:1	c.8321G>T	p.Arg2774Leu	missense	Exon 64 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460742

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111978

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.49

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.045

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.18

M_CAP

Benign

0.037

MetaRNN

Benign

0.097

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.63

PhyloP100

-0.12

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

REVEL

Benign

0.13

Sift

Benign

0.20

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.13

MutPred

0.45

Loss of MoRF binding (P = 0.0122)

MVP

0.66

MPC

0.24

ClinPred

0.053

GERP RS

-0.39

Varity_R

0.072

gMVP

0.47

Mutation Taster

=91/9

polymorphism

(source)

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

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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