14-91869710-T-C

Variant names:

• chr14-91869710-T-C
• rs17804735
• NM_006329.4:c.*514A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006329.4(FBLN5):​c.*514A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 162,658 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (35 hom., cov: 32)
  • Exomes 𝑓: 0.019 (2 hom.)
• Consequence: FBLN5 NM_006329.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-91869710-T-C is Benign according to our data. Variant chr14-91869710-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 314864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2535/152324) while in subpopulation NFE AF= 0.026 (1766/68032). AF 95% confidence interval is 0.0249. There are 35 homozygotes in gnomad4. There are 1175 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.*514A>G		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.*514A>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_006329.4	ENSP00000345008.4

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2532 AN: 152206 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0187 AC: 193 AN: 10334 Hom.: 2 Cov.: 0 AF XY: 0.0155 AC XY: 82 AN XY: 5290

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.00725

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00495

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0248

Gnomad4 OTH exome AF: 0.0246

GnomAD4 genome AF: 0.0166 AC: 2535 AN: 152324 Hom.: 35 Cov.: 32 AF XY: 0.0158 AC XY: 1175 AN XY: 74486

Gnomad4 AFR AF: 0.00491

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0260

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0229 Hom.: 13

Bravo AF: 0.0166

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely 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

May 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.75
CADD	Benign	14
DANN	Benign	0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17804735; hg19: chr14-92336054;