chr3-58008864-C-A

Variant names:

• chr3-58008864-C-A
• rs9831243
• NM_001457.4:c.292+8C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001457.4(FLNB):​c.292+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,613,484 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (83 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (76 hom.)
• Consequence: FLNB NM_001457.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006475
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.265
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-58008864-C-A is Benign according to our data. Variant chr3-58008864-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

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.292+8C>A		splice_region intron	N/A	NP_001448.2	O75369-1
	FLNB	NM_001164317.2		c.292+8C>A		splice_region intron	N/A	NP_001157789.1	O75369-8
	FLNB	NM_001164318.2		c.292+8C>A		splice_region intron	N/A	NP_001157790.1	O75369-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNB	ENST00000295956.9	TSL:1 MANE Select	c.292+8C>A		splice_region intron	N/A	ENSP00000295956.5	O75369-1
	FLNB	ENST00000490882.5	TSL:1	c.292+8C>A		splice_region intron	N/A	ENSP00000420213.1	O75369-8
	FLNB	ENST00000429972.6	TSL:1	c.292+8C>A		splice_region intron	N/A	ENSP00000415599.2	O75369-9

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2485 AN: 152190 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.0571

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

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: 0.000176

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00427 AC: 1068 AN: 250162 AF XY: 0.00318

Gnomad AFR exome AF: 0.0597

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00172 AC: 2516 AN: 1461176 Hom.: 76 Cov.: 31 AF XY: 0.00146 AC XY: 1062 AN XY: 726918

African (AFR) AF: 0.0618 AC: 2068 AN: 33476

American (AMR) AF: 0.00237 AC: 106 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52824

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111936

Other (OTH) AF: 0.00439 AC: 265 AN: 60384

GnomAD4 genome AF: 0.0164 AC: 2503 AN: 152308 Hom.: 83 Cov.: 33 AF XY: 0.0166 AC XY: 1233 AN XY: 74476

African (AFR) AF: 0.0573 AC: 2383 AN: 41552

American (AMR) AF: 0.00569 AC: 87 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68032

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00701 Hom.: 17

Bravo AF: 0.0191

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	FLNB-Related Spectrum Disorders (1)
-	-	1	Larsen syndrome;C0265283:Atelosteogenesis type I;C0432201:Boomerang dysplasia;C1848934:Spondylocarpotarsal synostosis syndrome;C3668942:Atelosteogenesis type III (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.2
DANN	Benign	0.92
PhyloP100		-0.27
PromoterAI		0.0046	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.15
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: rs9831243; hg19: chr3-57994591;