3-58008470-C-G

Position:

• chr3-58008470-C-G

Variant summary

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

The NM_001457.4(FLNB):​c.-95C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,436,968 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: FLNB NM_001457.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.33

Genes affected

FLNB (HGNC:3755): (filamin B) This gene encodes a member of the filamin family. The encoded protein interacts with glycoprotein Ib alpha as part of the process to repair vascular injuries. The platelet glycoprotein Ib complex includes glycoprotein Ib alpha, and it binds the actin cytoskeleton. Mutations in this gene have been found in several conditions: atelosteogenesis type 1 and type 3; boomerang dysplasia; autosomal dominant Larsen syndrome; and spondylocarpotarsal synostosis syndrome. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-58008470-C-G is Benign according to our data. Variant chr3-58008470-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 346293.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-58008470-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00144 (219/152290) while in subpopulation AMR AF= 0.00222 (34/15306). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNB	NM_001457.4	c.-95C>G		5_prime_UTR_variant	1/46	ENST00000295956.9
FLNB	NM_001164317.2	c.-95C>G		5_prime_UTR_variant	1/47
FLNB	NM_001164318.2	c.-95C>G		5_prime_UTR_variant	1/46
FLNB	NM_001164319.2	c.-95C>G		5_prime_UTR_variant	1/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9	c.-95C>G		5_prime_UTR_variant	1/46	1	NM_001457.4	A1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00137 AC: 1762 AN: 1284678 Hom.: 2 Cov.: 19 AF XY: 0.00136 AC XY: 871 AN XY: 639150

Gnomad4 AFR exome AF: 0.000205

Gnomad4 AMR exome AF: 0.00180

Gnomad4 ASJ exome AF: 0.000286

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000914

Gnomad4 FIN exome AF: 0.00396

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74468

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00139

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FLNB-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs528555050; hg19: chr3-57994197;