22-45518791-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006486.3(FBLN1):c.185+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,602,454 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: FBLN1 NM_006486.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00006927
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.27

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 22-45518791-C-T is Benign according to our data. Variant chr22-45518791-C-T is described in ClinVar as [Benign]. Clinvar id is 787509.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 414 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLN1	ENST00000327858.11	c.185+4C>T		splice_donor_region_variant, intron_variant		1	NM_006486.3	P1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000639 AC: 148 AN: 231528 Hom.: 0 AF XY: 0.000504 AC XY: 63 AN XY: 124888

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.000610

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: 0.0000578

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000267 AC: 387 AN: 1450152 Hom.: 1 Cov.: 31 AF XY: 0.000236 AC XY: 170 AN XY: 720612

Gnomad4 AFR exome AF: 0.00862

Gnomad4 AMR exome AF: 0.000666

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000235

Gnomad4 OTH exome AF: 0.000734

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152302 Hom.: 3 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74468

Gnomad4 AFR AF: 0.00953

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00306

Asia WGS AF: 0.000577 AC: 2 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

Invitae

Jun 26, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.19
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.022
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: rs147045275; hg19: chr22-45914671;