chr3-58008534-C-T

Position:

• chr3-58008534-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001457.4(FLNB):​c.-31C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,562,480 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (9 hom.)
• Consequence: FLNB NM_001457.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.147

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 3-58008534-C-T is Benign according to our data. Variant chr3-58008534-C-T is described in ClinVar as [Benign]. Clinvar id is 346296.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 = 0.00746 (1137/152354) while in subpopulation AFR AF= 0.0255 (1062/41586). AF 95% confidence interval is 0.0243. There are 14 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNB	NM_001457.4	c.-31C>T		5_prime_UTR_variant	1/46	ENST00000295956.9
FLNB	NM_001164317.2	c.-31C>T		5_prime_UTR_variant	1/47
FLNB	NM_001164318.2	c.-31C>T		5_prime_UTR_variant	1/46
FLNB	NM_001164319.2	c.-31C>T		5_prime_UTR_variant	1/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9	c.-31C>T		5_prime_UTR_variant	1/46	1	NM_001457.4	A1

Frequencies

GnomAD3 genomes AF: 0.00746 AC: 1136 AN: 152236 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00169 AC: 296 AN: 175544 Hom.: 2 AF XY: 0.00127 AC XY: 119 AN XY: 93604

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.000733 AC: 1034 AN: 1410126 Hom.: 9 Cov.: 31 AF XY: 0.000663 AC XY: 462 AN XY: 697194

Gnomad4 AFR exome AF: 0.0259

Gnomad4 AMR exome AF: 0.00133

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000988

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000469

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00746 AC: 1137 AN: 152354 Hom.: 14 Cov.: 33 AF XY: 0.00723 AC XY: 539 AN XY: 74506

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00397 Hom.: 1

Bravo AF: 0.00876

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

FLNB-Related Spectrum Disorders 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.1
DANN	Benign	0.94
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: rs138060096; hg19: chr3-57994261;