Genetic Variant NM_006486.3:c.32C>T (chr22-45503017-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006486.3(FBLN1):c.32C>T(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,247,254 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.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FBLN1
NM_006486.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0300

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25556856).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN1	NM_006486.3 link	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 17	ENST00000327858.11	NP_006477.3	P23142-1Q8NBH6
FBLN1	NM_001996.4 link	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 15		NP_001987.3	P23142-4A0A8S0LWY1
FBLN1	NM_006485.4 link	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 15		NP_006476.3	P23142-3Q8NBH6
FBLN1	NM_006487.3 link	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 15		NP_006478.3	P23142-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN1	ENST00000327858.11 link	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 17	1	NM_006486.3	ENSP00000331544.6		P23142-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151396

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1095858

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

525400

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000140

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151396

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73962

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

T;.;.;T;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.80

T;T;T;T;T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.26

T;T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.55

.;.;N;N;N;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.6

N;N;N;N;N;N

REVEL

Benign

0.28

Sift

Uncertain

0.0030

D;D;D;D;T;T

Sift4G

Uncertain

0.023

D;D;T;T;D;D

Polyphen

0.0010

.;B;B;B;.;.

Vest4

0.085, 0.10, 0.070, 0.13, 0.076

MutPred

0.48

Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);

MVP

0.70

MPC

0.39

ClinPred

0.28

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.065

gMVP

0.35

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over