rs74071606

Variant names:

• chr14-91881431-G-A
• rs74071606
• NM_006329.4:c.863-13C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384158.1(FBLN5):​c.986-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,614,058 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (52 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: FBLN5 NM_001384158.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.786
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 14-91881431-G-A is Benign according to our data. Variant chr14-91881431-G-A is described in ClinVar as Benign. ClinVar VariationId is 163456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1892/152306) while in subpopulation AFR AF = 0.0435 (1806/41556). AF 95% confidence interval is 0.0418. There are 52 homozygotes in GnomAd4. There are 885 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384158.1. 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.863-13C>T		intron	N/A	NP_006320.2
	FBLN5	NM_001384158.1		c.986-13C>T		intron	N/A	NP_001371087.1
	FBLN5	NM_001384159.1		c.914-13C>T		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.863-13C>T		intron	N/A	ENSP00000345008.4
	FBLN5	ENST00000267620.14	TSL:1	c.986-13C>T		intron	N/A	ENSP00000267620.10
	FBLN5	ENST00000556154.5	TSL:1	c.914-13C>T		intron	N/A	ENSP00000451982.2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1892 AN: 152188 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00341 AC: 857 AN: 251312 AF XY: 0.00250

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00141 AC: 2060 AN: 1461752 Hom.: 32 Cov.: 35 AF XY: 0.00118 AC XY: 857 AN XY: 727186

African (AFR) AF: 0.0479 AC: 1604 AN: 33480

American (AMR) AF: 0.00206 AC: 92 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.000169 AC: 188 AN: 1111964

Other (OTH) AF: 0.00280 AC: 169 AN: 60390

GnomAD4 genome AF: 0.0124 AC: 1892 AN: 152306 Hom.: 52 Cov.: 33 AF XY: 0.0119 AC XY: 885 AN XY: 74474

African (AFR) AF: 0.0435 AC: 1806 AN: 41556

American (AMR) AF: 0.00327 AC: 50 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

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: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00614 Hom.: 6

Bravo AF: 0.0141

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cutis laxa (1)
-	-	1	Macular degeneration, age-related, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		0.79
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: rs74071606; hg19: chr14-92347775;