Variant chr3-13570425-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001004019.2(FBLN2):c.70G>A(p.Val24Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000087 in 1,574,332 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

FBLN2
NM_001004019.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.75

Variant links:

Genes affected

FBLN2 (HGNC:3601): (fibulin 2) This gene encodes an extracellular matrix protein, which belongs to the fibulin family. This protein binds various extracellular ligands and calcium. It may play a role during organ development, in particular, during the differentiation of heart, skeletal and neuronal structures. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

FBLN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018014044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FBLN2	NM_001004019.2 linkuse as main transcript	c.70G>A	p.Val24Met	missense_variant	2/18	ENST00000404922.8
FBLN2	NM_001165035.2 linkuse as main transcript	c.70G>A	p.Val24Met	missense_variant	2/18
FBLN2	NM_001998.3 linkuse as main transcript	c.70G>A	p.Val24Met	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLN2	ENST00000404922.8 linkuse as main transcript	c.70G>A	p.Val24Met	missense_variant	2/18	5	NM_001004019.2	P1	P98095-2
FBLN2	ENST00000295760.11 linkuse as main transcript	c.70G>A	p.Val24Met	missense_variant	2/17	1			P98095-1
FBLN2	ENST00000492059.5 linkuse as main transcript	c.70G>A	p.Val24Met	missense_variant	2/18	2		P1	P98095-2
FBLN2	ENST00000465610.1 linkuse as main transcript	c.70G>A	p.Val24Met	missense_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

179644

Hom.:

AF XY:

0.000153

AC XY:

AN XY:

98226

show subpopulations

Gnomad AFR exome

AF:

0.000634

Gnomad AMR exome

AF:

0.000107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000739

Gnomad SAS exome

AF:

0.000366

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000796

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000795

AC:

113

AN:

1422046

Hom.:

Cov.:

AF XY:

0.0000796

AC XY:

AN XY:

703440

show subpopulations

Gnomad4 AFR exome

AF:

0.000641

Gnomad4 AMR exome

AF:

0.000101

Gnomad4 ASJ exome

AF:

0.0000393

Gnomad4 EAS exome

AF:

0.0000529

Gnomad4 SAS exome

AF:

0.000148

Gnomad4 FIN exome

AF:

0.0000209

Gnomad4 NFE exome

AF:

0.0000631

Gnomad4 OTH exome

AF:

0.0000510

GnomAD4 genome

AF:

0.000158

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000765

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000162

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.70G>A (p.V24M) alteration is located in exon 2 (coding exon 1) of the FBLN2 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the valine (V) at amino acid position 24 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.035

DANN

Benign

0.69

DEOGEN2

Benign

0.091

.;T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.45

.;T;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.20

N;N;.;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.020

N;N;N;N

REVEL

Benign

0.017

Sift

Benign

0.23

T;T;T;T

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.0010

B;B;.;B

Vest4

0.076

MVP

0.41

MPC

0.12

ClinPred

0.0078

GERP RS

-8.4

Varity_R

0.023

gMVP

0.11

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over