rs2430347

Variant names:

• chr14-91881336-A-G
• rs2430347
• NM_006329.4:c.945T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-91881336-A-G
• chr14-91881336-A-C
• chr14-91881336-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006329.4(FBLN5):​c.945T>C​(p.Ile315Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,613,648 control chromosomes in the GnomAD database, including 449,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44423 hom., cov: 32)
  • Exomes 𝑓: 0.74 (404882 hom.)
• Consequence: FBLN5 NM_006329.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.509
• Publications: 27 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 14-91881336-A-G is Benign according to our data. Variant chr14-91881336-A-G is described in ClinVar as Benign. ClinVar VariationId is 163450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.509 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN5	NM_006329.4	MANE Select	c.945T>C	p.Ile315Ile	synonymous	Exon 9 of 11	NP_006320.2
	FBLN5	NM_001384158.1		c.1068T>C	p.Ile356Ile	synonymous	Exon 10 of 12	NP_001371087.1	G3XA98
	FBLN5	NM_001384159.1		c.996T>C	p.Ile332Ile	synonymous	Exon 9 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.945T>C	p.Ile315Ile	synonymous	Exon 9 of 11	ENSP00000345008.4	Q9UBX5
	FBLN5	ENST00000267620.14	TSL:1	c.1068T>C	p.Ile356Ile	synonymous	Exon 10 of 12	ENSP00000267620.10	G3XA98
	FBLN5	ENST00000556154.5	TSL:1	c.996T>C	p.Ile332Ile	synonymous	Exon 9 of 11	ENSP00000451982.2	G3V4U0

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115905 AN: 152020 Hom.: 44362 Cov.: 32

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.829

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.751

GnomAD2 exomes AF: 0.764 AC: 191914 AN: 251290 AF XY: 0.756

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.876

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.835

Gnomad FIN exome AF: 0.749

Gnomad NFE exome AF: 0.737

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.743 AC: 1085841 AN: 1461510 Hom.: 404882 Cov.: 46 AF XY: 0.742 AC XY: 539652 AN XY: 727084

African (AFR) AF: 0.782 AC: 26187 AN: 33474

American (AMR) AF: 0.868 AC: 38841 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 16747 AN: 26126

East Asian (EAS) AF: 0.864 AC: 34288 AN: 39698

South Asian (SAS) AF: 0.737 AC: 63523 AN: 86248

European-Finnish (FIN) AF: 0.754 AC: 40258 AN: 53408

Middle Eastern (MID) AF: 0.711 AC: 4100 AN: 5768

European-Non Finnish (NFE) AF: 0.735 AC: 817074 AN: 1111680

Other (OTH) AF: 0.742 AC: 44823 AN: 60384

GnomAD4 genome AF: 0.763 AC: 116030 AN: 152138 Hom.: 44423 Cov.: 32 AF XY: 0.763 AC XY: 56737 AN XY: 74364

African (AFR) AF: 0.787 AC: 32633 AN: 41480

American (AMR) AF: 0.830 AC: 12684 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2222 AN: 3472

East Asian (EAS) AF: 0.840 AC: 4351 AN: 5180

South Asian (SAS) AF: 0.739 AC: 3562 AN: 4822

European-Finnish (FIN) AF: 0.737 AC: 7797 AN: 10584

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.741 AC: 50386 AN: 68000

Other (OTH) AF: 0.754 AC: 1589 AN: 2108

Alfa AF: 0.746 Hom.: 89567

Bravo AF: 0.771

Asia WGS AF: 0.807 AC: 2806 AN: 3478

EpiCase AF: 0.728

EpiControl AF: 0.727

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Macular degeneration, age-related, 3 (2)
-	-	2	not provided (2)
-	-	1	Cutis laxa (1)
-	-	1	Cutis laxa, autosomal dominant 2 (1)
-	-	1	Cutis laxa, autosomal recessive, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.34
DANN	Benign	0.60
PhyloP100		-0.51
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: rs2430347; hg19: chr14-92347680; COSMIC: COSV50904887; COSMIC: COSV50904887;