NM_006486.3:c.58C>A

Variant names:

• chr22-45503043-C-A
• NM_006486.3:c.58C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006486.3(FBLN1):​c.58C>A​(p.Leu20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000909 in 1,099,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.356

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23050594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN1	NM_006486.3	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 17	ENST00000327858.11	NP_006477.3
FBLN1	NM_001996.4	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 15		NP_001987.3
FBLN1	NM_006485.4	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 15		NP_006476.3
FBLN1	NM_006487.3	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 15		NP_006478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN1	ENST00000327858.11	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 17	1	NM_006486.3	ENSP00000331544.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.09e-7 AC: 1 AN: 1099572 Hom.: 0 Cov.: 30 AF XY: 0.00000190 AC XY: 1 AN XY: 525446

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: 0.00000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.058	T;.;.;T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.62	T;T;T;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.23	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	.;.;N;N;N;N
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.24	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.24	T;T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T
Polyphen		0.036, 0.025, 0.014	.;B;B;B;.;.
Vest4		0.20, 0.25, 0.22, 0.22, 0.21
MutPred		0.67		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.38
MPC		0.42
ClinPred		0.084	T
GERP RS		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.061
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-45898923;