14-91869801-A-G

Position:

• chr14-91869801-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006329.4(FBLN5):​c.*423T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 245,426 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (3 hom.)
• Consequence: FBLN5 NM_006329.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.452

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-91869801-A-G is Benign according to our data. Variant chr14-91869801-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 314866.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00525 (799/152244) while in subpopulation NFE AF= 0.00907 (617/68008). AF 95% confidence interval is 0.00848. There are 2 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.*423T>C		3_prime_UTR_variant	11/11	ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9	c.*423T>C		3_prime_UTR_variant	11/11	1	NM_006329.4	ENSP00000345008	P1

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 799 AN: 152126 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00907

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00548 AC: 511 AN: 93182 Hom.: 3 Cov.: 0 AF XY: 0.00506 AC XY: 247 AN XY: 48780

Gnomad4 AFR exome AF: 0.000889

Gnomad4 AMR exome AF: 0.00517

Gnomad4 ASJ exome AF: 0.000843

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.00241

Gnomad4 NFE exome AF: 0.00784

Gnomad4 OTH exome AF: 0.00433

GnomAD4 genome AF: 0.00525 AC: 799 AN: 152244 Hom.: 2 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74430

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00359

Gnomad4 NFE AF: 0.00907

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00725 Hom.: 1

Bravo AF: 0.00529

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Macular degeneration, age-related, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cutis laxa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.80
CADD	Benign	2.2
DANN	Benign	0.36

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17731705; hg19: chr14-92336145;