chr3-58008534-C-T

Variant names:

• chr3-58008534-C-T
• rs138060096
• NM_001457.4:c.-31C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.147
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 46	NP_001448.2	O75369-1
	FLNB	NM_001457.4	MANE Select	c.-31C>T		5_prime_UTR	Exon 1 of 46	NP_001448.2	O75369-1
	FLNB	NM_001164317.2		c.-31C>T		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.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 46	ENSP00000295956.5	O75369-1
	FLNB	ENST00000490882.5	TSL:1	c.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 47	ENSP00000420213.1	O75369-8
	FLNB	ENST00000429972.6	TSL:1	c.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 46	ENSP00000415599.2	O75369-9

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

GnomAD2 exomes AF: 0.00169 AC: 296 AN: 175544 AF XY: 0.00127

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 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

African (AFR) AF: 0.0259 AC: 826 AN: 31936

American (AMR) AF: 0.00133 AC: 49 AN: 36726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 36432

South Asian (SAS) AF: 0.0000988 AC: 8 AN: 80968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49922

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4106

European-Non Finnish (NFE) AF: 0.0000469 AC: 51 AN: 1086298

Other (OTH) AF: 0.00169 AC: 99 AN: 58408

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

African (AFR) AF: 0.0255 AC: 1062 AN: 41586

American (AMR) AF: 0.00281 AC: 43 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00418 Hom.: 1

Bravo AF: 0.00876

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	FLNB-Related Spectrum Disorders (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.1
DANN	Benign	0.94
PhyloP100		0.15
PromoterAI		-0.015	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: rs138060096; hg19: chr3-57994261;