22-45518795-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006486.3(FBLN1):c.185+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,597,416 control chromosomes in the GnomAD database, including 13,408 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4603 hom., cov: 32)
  • Exomes 𝑓: 0.093 (8805 hom.)
• Consequence: FBLN1 NM_006486.3 splice_region, intron
• Scores: Splicing: ADA: 0.00008021
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.213

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 22-45518795-T-C is Benign according to our data. Variant chr22-45518795-T-C is described in ClinVar as [Benign]. Clinvar id is 1286401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBLN1	NM_006486.3	c.185+8T>C		splice_region_variant, intron_variant		ENST00000327858.11
FBLN1	NM_001996.4	c.185+8T>C		splice_region_variant, intron_variant
FBLN1	NM_006485.4	c.185+8T>C		splice_region_variant, intron_variant
FBLN1	NM_006487.3	c.185+8T>C		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLN1	ENST00000327858.11	c.185+8T>C		splice_region_variant, intron_variant		1	NM_006486.3	P1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27925 AN: 152116 Hom.: 4583 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0882

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.0510

Gnomad SAS AF: 0.0671

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.0981 AC: 22276 AN: 226968 Hom.: 2053 AF XY: 0.0907 AC XY: 11095 AN XY: 122292

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.0521

Gnomad ASJ exome AF: 0.0679

Gnomad EAS exome AF: 0.0393

Gnomad SAS exome AF: 0.0644

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0838

Gnomad OTH exome AF: 0.0770

GnomAD4 exome AF: 0.0933 AC: 134869 AN: 1445182 Hom.: 8805 Cov.: 30 AF XY: 0.0908 AC XY: 65207 AN XY: 717998

Gnomad4 AFR exome AF: 0.452

Gnomad4 AMR exome AF: 0.0562

Gnomad4 ASJ exome AF: 0.0671

Gnomad4 EAS exome AF: 0.0639

Gnomad4 SAS exome AF: 0.0640

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.0869

Gnomad4 OTH exome AF: 0.0996

GnomAD4 genome AF: 0.184 AC: 28001 AN: 152234 Hom.: 4603 Cov.: 32 AF XY: 0.180 AC XY: 13382 AN XY: 74436

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.0881

Gnomad4 ASJ AF: 0.0718

Gnomad4 EAS AF: 0.0510

Gnomad4 SAS AF: 0.0671

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.0845

Gnomad4 OTH AF: 0.140

Alfa AF: 0.124 Hom.: 1097

Bravo AF: 0.192

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	6.1
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.070
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: rs78488153; hg19: chr22-45914675;