3-58008470-C-G

Variant names:

• chr3-58008470-C-G
• rs528555050
• NM_001457.4:c.-95C>G

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.33
• Publications: 0 publications found

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]

FLNB Gene-Disease associations (from GenCC):

• atelosteogenesis type I

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• atelosteogenesis type III

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Larsen syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• spondylocarpotarsal synostosis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Boomerang dysplasia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 346293.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001457.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNB	NM_001457.4	MANE Select	c.-95C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 46	NP_001448.2	O75369-1
	FLNB	NM_001457.4	MANE Select	c.-95C>G		5_prime_UTR	Exon 1 of 46	NP_001448.2	O75369-1
	FLNB	NM_001164317.2		c.-95C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 47	NP_001157789.1	O75369-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNB	ENST00000295956.9	TSL:1 MANE Select	c.-95C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 46	ENSP00000295956.5	O75369-1
	FLNB	ENST00000490882.5	TSL:1	c.-95C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 47	ENSP00000420213.1	O75369-8
	FLNB	ENST00000429972.6	TSL:1	c.-95C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 46	ENSP00000415599.2	O75369-9

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

African (AFR) AF: 0.000205 AC: 6 AN: 29288

American (AMR) AF: 0.00180 AC: 64 AN: 35540

Ashkenazi Jewish (ASJ) AF: 0.000286 AC: 7 AN: 24456

East Asian (EAS) AF: 0.00 AC: 0 AN: 35218

South Asian (SAS) AF: 0.0000914 AC: 7 AN: 76624

European-Finnish (FIN) AF: 0.00396 AC: 187 AN: 47248

Middle Eastern (MID) AF: 0.000519 AC: 2 AN: 3850

European-Non Finnish (NFE) AF: 0.00144 AC: 1408 AN: 978302

Other (OTH) AF: 0.00150 AC: 81 AN: 54152

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

African (AFR) AF: 0.000265 AC: 11 AN: 41580

American (AMR) AF: 0.00222 AC: 34 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00182 AC: 124 AN: 67986

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00139

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	FLNB-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		1.3
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs528555050; hg19: chr3-57994197;