rs121434299

Variant names:

• chr14-91937148-C-G
• rs121434299
• NM_006329.4:c.178G>C
• FBLN5 p.Val60Leu

Your query was ambiguous. Multiple possible variants found:

• chr14-91937148-C-G
• chr14-91937148-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006329.4(FBLN5):​c.178G>C​(p.Val60Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000651 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: FBLN5 NM_006329.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:3
• Conservation: PhyloP100: 5.75
• 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: AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.178G>C	p.Val60Leu	missense	Exon 4 of 11	NP_006320.2
	FBLN5	NM_001384158.1		c.301G>C	p.Val101Leu	missense	Exon 5 of 12	NP_001371087.1	G3XA98
	FBLN5	NM_001384159.1		c.229G>C	p.Val77Leu	missense	Exon 4 of 11	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.178G>C	p.Val60Leu	missense	Exon 4 of 11	ENSP00000345008.4	Q9UBX5
	FBLN5	ENST00000267620.14	TSL:1	c.301G>C	p.Val101Leu	missense	Exon 5 of 12	ENSP00000267620.10	G3XA98
	FBLN5	ENST00000556154.5	TSL:1	c.229G>C	p.Val77Leu	missense	Exon 4 of 11	ENSP00000451982.2	G3V4U0

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249054 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000705 AC: 103 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000872 AC: 97 AN: 1112012

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Age-related macular degeneration (1)
-	1	-	FBLN5-related disorder (1)
1	-	-	Macular degeneration, age-related, 3 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.61
Sift	Benign	0.077	T
Sift4G	Benign	0.099	T
Varity_R		0.38
gMVP		0.85
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121434299;

hg19: chr14-92403492;