Genetic Variant FBN3:p.Val938Phe (chr19-8123928-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_032447.5(FBN3):c.2812G>T(p.Val938Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,768 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. V938I) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.233

Publications

12 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37187514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.2812G>T	p.Val938Phe	missense_variant	Exon 23 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.2812G>T	p.Val938Phe	missense_variant	Exon 23 of 64	1	NM_032447.5	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6 link	c.2812G>T	p.Val938Phe	missense_variant	Exon 22 of 63	1		ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5 link	c.2812G>T	p.Val938Phe	missense_variant	Exon 23 of 64	1		ENSP00000472324.1	Q75N90
FBN3	ENST00000651877.1 link	c.2938G>T	p.Val980Phe	missense_variant	Exon 23 of 64			ENSP00000498507.1	A0A494C0D8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60396

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.90

.;.;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.3

M;M;M

PhyloP100

-0.23

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.3

.;N;.

REVEL

Uncertain

0.34

Sift

Benign

0.036

.;D;.

Sift4G

Benign

0.47

T;T;T

Polyphen

0.93

P;P;P

Vest4

0.40

MutPred

0.22

Loss of ubiquitination at K933 (P = 0.1287);Loss of ubiquitination at K933 (P = 0.1287);Loss of ubiquitination at K933 (P = 0.1287);

MVP

0.64

MPC

0.68

ClinPred

0.93

GERP RS

-0.095

Varity_R

0.19

gMVP

0.65

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over