22-45503047-C-T

Position:

chr22-45503047-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006486.3(FBLN1):c.62C>T(p.Ala21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,249,902 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

FBLN1
NM_006486.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.198

Variant links:

Genes affected

FBLN1 (HGNC:3600): (fibulin 1) Fibulin 1 is a secreted glycoprotein that becomes incorporated into a fibrillar extracellular matrix. Calcium-binding is apparently required to mediate its binding to laminin and nidogen. It mediates platelet adhesion via binding fibrinogen. Four splice variants which differ in the 3' end have been identified. Each variant encodes a different isoform, but no functional distinctions have been identified among the four variants. [provided by RefSeq, Jul 2008]

FBLN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0079521835).

BS2

High AC in GnomAd4 at 328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FBLN1	NM_006486.3 linkuse as main transcript	c.62C>T	p.Ala21Val	missense_variant	1/17	ENST00000327858.11
FBLN1	NM_001996.4 linkuse as main transcript	c.62C>T	p.Ala21Val	missense_variant	1/15
FBLN1	NM_006485.4 linkuse as main transcript	c.62C>T	p.Ala21Val	missense_variant	1/15
FBLN1	NM_006487.3 linkuse as main transcript	c.62C>T	p.Ala21Val	missense_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLN1	ENST00000327858.11 linkuse as main transcript	c.62C>T	p.Ala21Val	missense_variant	1/17	1	NM_006486.3	P1	P23142-1

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

328

AN:

151746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00751

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000985

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000442

AC:

AN:

13562

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

8484

show subpopulations

Gnomad AFR exome

AF:

0.00833

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000230

AC:

253

AN:

1098048

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

117

AN XY:

524534

show subpopulations

Gnomad4 AFR exome

AF:

0.00835

Gnomad4 AMR exome

AF:

0.00117

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000430

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.00216

AC:

328

AN:

151854

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.00749

Gnomad4 AMR

AF:

0.000983

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.00258

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 26, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1522584). This variant has not been reported in the literature in individuals affected with FBLN1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 21 of the FBLN1 protein (p.Ala21Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

T;.;.;T;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.71

T;T;T;T;T;T

MetaRNN

Benign

0.0080

T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.34

.;.;N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.51

N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.19

T;T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;T;T

Polyphen

0.0020, 0.0010, 0.0

.;B;B;B;.;.

Vest4

0.097, 0.13, 0.15, 0.13, 0.087

MutPred

0.67

Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);

MVP

0.63

MPC

0.38

ClinPred

0.016

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.048

gMVP

0.33

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