22-45503026-T-C

Position:

• chr22-45503026-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006486.3(FBLN1):​c.41T>C​(p.Leu14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.793

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27745152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN1	NM_006486.3	c.41T>C	p.Leu14Pro	missense_variant	1/17	ENST00000327858.11	NP_006477.3
FBLN1	NM_001996.4	c.41T>C	p.Leu14Pro	missense_variant	1/15		NP_001987.3
FBLN1	NM_006485.4	c.41T>C	p.Leu14Pro	missense_variant	1/15		NP_006476.3
FBLN1	NM_006487.3	c.41T>C	p.Leu14Pro	missense_variant	1/15		NP_006478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN1	ENST00000327858.11	c.41T>C	p.Leu14Pro	missense_variant	1/17	1	NM_006486.3	ENSP00000331544.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1099648 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 526964

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2024

The c.41T>C (p.L14P) alteration is located in exon 1 (coding exon 1) of the FBLN1 gene. This alteration results from a T to C substitution at nucleotide position 41, causing the leucine (L) at amino acid position 14 to be replaced by a proline (P). 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	0.14
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Benign	0.051	T;.;.;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.51	T;T;T;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.55	.;.;N;N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.23	N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.086	T;T;T;T;T;T
Sift4G	Uncertain	0.053	T;T;T;T;T;T
Polyphen		0.085, 0.14	.;B;B;B;.;.
Vest4		0.26, 0.19, 0.29, 0.36, 0.27
MutPred		0.61		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.59
MPC		0.63
ClinPred		0.13	T
GERP RS		0.055
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr22-45898906;