22-45563660-G-A

Variant names:

• chr22-45563660-G-A
• rs743931
• NM_006486.3:c.1698-10851G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006486.3(FBLN1):​c.1698-10851G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 152,112 control chromosomes in the GnomAD database, including 41,923 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (41923 hom., cov: 32)
• Consequence: FBLN1 NM_006486.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.95
• Publications: 7 publications found

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]

FBLN1 Gene-Disease associations (from GenCC):

• FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• synpolydactyly type 2

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN1	NM_006486.3	c.1698-10851G>A		intron_variant	Intron 14 of 16	ENST00000327858.11	NP_006477.3
FBLN1	NM_006485.4	c.1698-1224G>A		intron_variant	Intron 14 of 14		NP_006476.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN1	ENST00000327858.11	c.1698-10851G>A		intron_variant	Intron 14 of 16	1	NM_006486.3	ENSP00000331544.6
FBLN1	ENST00000442170.6	c.1698-1224G>A		intron_variant	Intron 14 of 14	1		ENSP00000393812.2

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112608 AN: 151994 Hom.: 41891 Cov.: 32

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.725

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.694

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.736

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.741 AC: 112686 AN: 152112 Hom.: 41923 Cov.: 32 AF XY: 0.741 AC XY: 55132 AN XY: 74358

African (AFR) AF: 0.822 AC: 34105 AN: 41510

American (AMR) AF: 0.670 AC: 10247 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 2517 AN: 3472

East Asian (EAS) AF: 0.660 AC: 3402 AN: 5156

South Asian (SAS) AF: 0.694 AC: 3339 AN: 4814

European-Finnish (FIN) AF: 0.751 AC: 7957 AN: 10602

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48644 AN: 67950

Other (OTH) AF: 0.733 AC: 1547 AN: 2110

Alfa AF: 0.723 Hom.: 119310

Bravo AF: 0.740

Asia WGS AF: 0.642 AC: 2234 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0030
DANN	Benign	0.54
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs743931; hg19: chr22-45959540;