rs2246416

Variant names:

• chr14-91924276-A-G
• rs2246416
• NM_006329.4:c.379+12671T>C

Variant summary

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

The NM_006329.4(FBLN5):​c.379+12671T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,196 control chromosomes in the GnomAD database, including 7,110 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 0.30 (7110 hom., cov: 33)
• Consequence: FBLN5 NM_006329.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359
• Publications: 6 publications found

Genes affected

FBLN5 (HGNC:3602): (fibulin 5) The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3). [provided by RefSeq, Jul 2008]

FBLN5 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• cutis laxa, autosomal recessive, type 1A

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Charcot-Marie-Tooth disease, demyelinating, IIA 1H

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• demyelinating hereditary motor and sensory neuropathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• macular degeneration, age-related, 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensorimotor neuropathy with hyperelastic skin

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive cutis laxa type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006329.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN5	NM_006329.4	MANE Select	c.379+12671T>C		intron	N/A	NP_006320.2
	FBLN5	NM_001384158.1		c.502+12671T>C		intron	N/A	NP_001371087.1
	FBLN5	NM_001384159.1		c.430+12671T>C		intron	N/A	NP_001371088.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN5	ENST00000342058.9	TSL:1 MANE Select	c.379+12671T>C		intron	N/A	ENSP00000345008.4
	FBLN5	ENST00000267620.14	TSL:1	c.502+12671T>C		intron	N/A	ENSP00000267620.10
	FBLN5	ENST00000556154.5	TSL:1	c.430+12671T>C		intron	N/A	ENSP00000451982.2

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46101 AN: 152078 Hom.: 7109 Cov.: 33

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.303 AC: 46113 AN: 152196 Hom.: 7110 Cov.: 33 AF XY: 0.305 AC XY: 22661 AN XY: 74404

African (AFR) AF: 0.280 AC: 11609 AN: 41524

American (AMR) AF: 0.288 AC: 4404 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1292 AN: 3472

East Asian (EAS) AF: 0.482 AC: 2489 AN: 5168

South Asian (SAS) AF: 0.392 AC: 1891 AN: 4826

European-Finnish (FIN) AF: 0.297 AC: 3148 AN: 10594

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20198 AN: 68006

Other (OTH) AF: 0.316 AC: 667 AN: 2108

Alfa AF: 0.302 Hom.: 5565

Bravo AF: 0.304

Asia WGS AF: 0.412 AC: 1434 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.75
PhyloP100		0.36
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: rs2246416; hg19: chr14-92390620;