rs147699855

Variant names:

• chr14-91887320-A-G
• rs147699855
• NM_006329.4:c.620-8T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006329.4(FBLN5):​c.620-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,612,438 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00052 (4 hom.)
• Consequence: FBLN5 NM_006329.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002825
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.42
• Publications: 0 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: AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-91887320-A-G is Benign according to our data. Variant chr14-91887320-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN5	NM_006329.4	MANE Select	c.620-8T>C		splice_region intron	N/A	NP_006320.2
	FBLN5	NM_001384158.1		c.743-8T>C		splice_region intron	N/A	NP_001371087.1	G3XA98
	FBLN5	NM_001384159.1		c.671-8T>C		splice_region intron	N/A	NP_001371088.1	G3V4U0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN5	ENST00000342058.9	TSL:1 MANE Select	c.620-8T>C		splice_region intron	N/A	ENSP00000345008.4	Q9UBX5
	FBLN5	ENST00000267620.14	TSL:1	c.743-8T>C		splice_region intron	N/A	ENSP00000267620.10	G3XA98
	FBLN5	ENST00000556154.5	TSL:1	c.671-8T>C		splice_region intron	N/A	ENSP00000451982.2	G3V4U0

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 470 AN: 151990 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00952

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00520

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00121 AC: 304 AN: 250476 AF XY: 0.00105

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000521 AC: 761 AN: 1460330 Hom.: 4 Cov.: 32 AF XY: 0.000483 AC XY: 351 AN XY: 726496

African (AFR) AF: 0.00881 AC: 295 AN: 33478

American (AMR) AF: 0.00103 AC: 46 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00448 AC: 117 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00184 AC: 159 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52106

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111826

Other (OTH) AF: 0.00147 AC: 89 AN: 60366

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152108 Hom.: 2 Cov.: 31 AF XY: 0.00281 AC XY: 209 AN XY: 74356

African (AFR) AF: 0.00957 AC: 397 AN: 41498

American (AMR) AF: 0.00268 AC: 41 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 18 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67982

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00181 Hom.: 1

Bravo AF: 0.00346

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cutis laxa (1)
-	-	1	FBLN5-related disorder (1)
-	-	1	Macular degeneration, age-related, 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.61
PhyloP100		2.4
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.020		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: rs147699855; hg19: chr14-92353664;