14-91941349-C-T

Variant names:

• chr14-91941349-C-T
• rs3783937
• NM_006329.4:c.73-733G>A

Variant summary

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

The NM_006329.4(FBLN5):​c.73-733G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 151,970 control chromosomes in the GnomAD database, including 3,215 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 0.19 (3215 hom., cov: 31)
• Consequence: FBLN5 NM_006329.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.675
• Publications: 11 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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 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.73-733G>A		intron	N/A	NP_006320.2
	FBLN5	NM_001384158.1		c.73-733G>A		intron	N/A	NP_001371087.1
	FBLN5	NM_001384159.1		c.124-733G>A		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.73-733G>A		intron	N/A	ENSP00000345008.4
	FBLN5	ENST00000267620.14	TSL:1	c.73-733G>A		intron	N/A	ENSP00000267620.10
	FBLN5	ENST00000556154.5	TSL:1	c.124-733G>A		intron	N/A	ENSP00000451982.2

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29093 AN: 151852 Hom.: 3220 Cov.: 31

Gnomad AFR AF: 0.0685

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.191 AC: 29079 AN: 151970 Hom.: 3215 Cov.: 31 AF XY: 0.195 AC XY: 14453 AN XY: 74262

African (AFR) AF: 0.0684 AC: 2836 AN: 41474

American (AMR) AF: 0.165 AC: 2520 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 1248 AN: 3462

East Asian (EAS) AF: 0.211 AC: 1089 AN: 5164

South Asian (SAS) AF: 0.302 AC: 1452 AN: 4806

European-Finnish (FIN) AF: 0.262 AC: 2763 AN: 10550

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16378 AN: 67948

Other (OTH) AF: 0.213 AC: 450 AN: 2110

Alfa AF: 0.227 Hom.: 7206

Bravo AF: 0.177

Asia WGS AF: 0.212 AC: 738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.71
PhyloP100		0.68
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: rs3783937; hg19: chr14-92407693;