22-45518812-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006486.3(FBLN1):c.185+25T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0707 in 1,548,336 control chromosomes in the GnomAD database, including 4,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.063 (369 hom., cov: 32)
  • Exomes 𝑓: 0.072 (3935 hom.)
• Consequence: FBLN1 NM_006486.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.649

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-45518812-T-G is Benign according to our data. Variant chr22-45518812-T-G is described in ClinVar as [Benign]. Clinvar id is 1279638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBLN1	NM_006486.3	c.185+25T>G		intron_variant		ENST00000327858.11
FBLN1	NM_001996.4	c.185+25T>G		intron_variant
FBLN1	NM_006485.4	c.185+25T>G		intron_variant
FBLN1	NM_006487.3	c.185+25T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLN1	ENST00000327858.11	c.185+25T>G		intron_variant		1	NM_006486.3	P1

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9630 AN: 152132 Hom.: 369 Cov.: 32

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0766

Gnomad OTH AF: 0.0502

GnomAD3 exomes AF: 0.0572 AC: 11766 AN: 205682 Hom.: 410 AF XY: 0.0556 AC XY: 6132 AN XY: 110290

Gnomad AFR exome AF: 0.0502

Gnomad AMR exome AF: 0.0303

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.00340

Gnomad SAS exome AF: 0.0183

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0771

Gnomad OTH exome AF: 0.0546

GnomAD4 exome AF: 0.0715 AC: 99885 AN: 1396086 Hom.: 3935 Cov.: 25 AF XY: 0.0696 AC XY: 48334 AN XY: 694202

Gnomad4 AFR exome AF: 0.0517

Gnomad4 AMR exome AF: 0.0310

Gnomad4 ASJ exome AF: 0.0445

Gnomad4 EAS exome AF: 0.00297

Gnomad4 SAS exome AF: 0.0180

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.0800

Gnomad4 OTH exome AF: 0.0619

GnomAD4 genome AF: 0.0633 AC: 9633 AN: 152250 Hom.: 369 Cov.: 32 AF XY: 0.0629 AC XY: 4682 AN XY: 74438

Gnomad4 AFR AF: 0.0529

Gnomad4 AMR AF: 0.0410

Gnomad4 ASJ AF: 0.0458

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.0152

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.0767

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0651 Hom.: 89

Bravo AF: 0.0581

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.11
Dann	Benign	0.44

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: rs77035925; hg19: chr22-45914692;