22-45503059-C-T

Position:

• chr22-45503059-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006486.3(FBLN1):​c.74C>T​(p.Ala25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000616 in 1,246,944 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 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045414567).
• BS2: High AC in GnomAd4 at 474 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN1	NM_006486.3	c.74C>T	p.Ala25Val	missense_variant	1/17	ENST00000327858.11	NP_006477.3
FBLN1	NM_001996.4	c.74C>T	p.Ala25Val	missense_variant	1/15		NP_001987.3
FBLN1	NM_006485.4	c.74C>T	p.Ala25Val	missense_variant	1/15		NP_006476.3
FBLN1	NM_006487.3	c.74C>T	p.Ala25Val	missense_variant	1/15		NP_006478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN1	ENST00000327858.11	c.74C>T	p.Ala25Val	missense_variant	1/17	1	NM_006486.3	ENSP00000331544.6

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 474 AN: 151820 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000119 AC: 1 AN: 8396 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 5306

Gnomad AFR exome AF: 0.00781

Gnomad AMR exome AF: 0.00

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: 0.000268 AC: 294 AN: 1095018 Hom.: 2 Cov.: 30 AF XY: 0.000241 AC XY: 126 AN XY: 522636

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000310

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: 0.00000108

Gnomad4 OTH exome AF: 0.000550

GnomAD4 genome AF: 0.00312 AC: 474 AN: 151926 Hom.: 1 Cov.: 32 AF XY: 0.00323 AC XY: 240 AN XY: 74256

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000418 Hom.: 0

Bravo AF: 0.00353

ExAC AF: 0.000340 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 25 of the FBLN1 protein (p.Ala25Val). 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 variant has not been reported in the literature in individuals affected with FBLN1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T;.;.;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.61	T;T;T;T;T;T
MetaRNN	Benign	0.0045	T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.69	.;.;N;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.049	D;D;T;T;D;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.94, 0.93, 0.72	.;P;P;P;.;.
Vest4		0.24, 0.27, 0.30, 0.33, 0.24
MVP		0.76
MPC		0.38
ClinPred		0.039	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.084
gMVP		0.27

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

Other links and lift over

dbSNP: rs528661383; hg19: chr22-45898939;