rs116826041

Variant names:

• chr3-58159621-T-C
• rs116826041
• NM_001457.4:c.6956T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001457.4(FLNB):​c.6956T>C​(p.Ile2319Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00944 in 1,614,004 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (99 hom.)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 8.02
• Publications: 18 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 (MetaRNN=0.009274721).
• BP6: Variant 3-58159621-T-C is Benign according to our data. Variant chr3-58159621-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0072 (1096/152214) while in subpopulation AMR AF = 0.00967 (148/15298). AF 95% confidence interval is 0.00882. There are 10 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR 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.6956T>C	p.Ile2319Thr	missense	Exon 42 of 46	NP_001448.2	O75369-1
	FLNB	NM_001164317.2		c.7049T>C	p.Ile2350Thr	missense	Exon 43 of 47	NP_001157789.1	O75369-8
	FLNB	NM_001164318.2		c.6923T>C	p.Ile2308Thr	missense	Exon 42 of 46	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.6956T>C	p.Ile2319Thr	missense	Exon 42 of 46	ENSP00000295956.5	O75369-1
	FLNB	ENST00000490882.5	TSL:1	c.7049T>C	p.Ile2350Thr	missense	Exon 43 of 47	ENSP00000420213.1	O75369-8
	FLNB	ENST00000429972.6	TSL:1	c.6923T>C	p.Ile2308Thr	missense	Exon 42 of 46	ENSP00000415599.2	O75369-9

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1097 AN: 152096 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00743 AC: 1867 AN: 251130 AF XY: 0.00706

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00781

Gnomad ASJ exome AF: 0.0448

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00868

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00968 AC: 14146 AN: 1461790 Hom.: 99 Cov.: 34 AF XY: 0.00948 AC XY: 6894 AN XY: 727196

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.00832 AC: 372 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 1191 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86258

European-Finnish (FIN) AF: 0.00167 AC: 89 AN: 53344

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5766

European-Non Finnish (NFE) AF: 0.0106 AC: 11749 AN: 1111990

Other (OTH) AF: 0.0104 AC: 628 AN: 60392

GnomAD4 genome AF: 0.00720 AC: 1096 AN: 152214 Hom.: 10 Cov.: 32 AF XY: 0.00657 AC XY: 489 AN XY: 74416

African (AFR) AF: 0.00222 AC: 92 AN: 41518

American (AMR) AF: 0.00967 AC: 148 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00943 AC: 641 AN: 68008

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00943 Hom.: 36

Bravo AF: 0.00751

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00648 AC: 787

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0103

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Connective tissue disorder (1)
-	-	1	FLNB-Related Spectrum Disorders (1)
-	-	1	Larsen syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.78	P
Vest4		0.83
MVP		0.94
MPC		0.81
ClinPred		0.020	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.66
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116826041; hg19: chr3-58145348; COSMIC: COSV55888965; COSMIC: COSV55888965;