14-91869895-A-G

Variant names:

• chr14-91869895-A-G
• rs115237925
• NM_006329.4:c.*329T>C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_006329.4(FBLN5):​c.*329T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0162 in 365,374 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 32)
  • Exomes 𝑓: 0.018 (162 hom.)
• Consequence: FBLN5 NM_006329.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.47

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-91869895-A-G is Benign according to our data. Variant chr14-91869895-A-G is described in ClinVar as [Benign]. Clinvar id is 314868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.*329T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058	c.*329T>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_006329.4	ENSP00000345008.4

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2086 AN: 152158 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0765

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.0179 AC: 3824 AN: 213098 Hom.: 162 Cov.: 0 AF XY: 0.0244 AC XY: 2830 AN XY: 116028

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.00254

Gnomad4 ASJ exome AF: 0.000196

Gnomad4 EAS exome AF: 0.0261

Gnomad4 SAS exome AF: 0.0760

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000796

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.0138 AC: 2104 AN: 152276 Hom.: 49 Cov.: 32 AF XY: 0.0150 AC XY: 1119 AN XY: 74464

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0270

Gnomad4 SAS AF: 0.0769

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.0133

Asia WGS AF: 0.0570 AC: 201 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Macular degeneration, age-related, 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cutis laxa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.80

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs115237925; hg19: chr14-92336239;