rs62621999

Variant names:

• chr3-58106851-C-T
• rs62621999
• NM_001457.4:c.1919C>T

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.1919C>T​(p.Thr640Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,613,808 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T640T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.46
• Publications: 8 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)

ENSG00000303089 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042644143).
• BP6: Variant 3-58106851-C-T is Benign according to our data. Variant chr3-58106851-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 346316.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 = 0.00868 (1322/152274) while in subpopulation AFR AF = 0.0302 (1255/41536). AF 95% confidence interval is 0.0288. There are 22 homozygotes in GnomAd4. There are 634 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.1919C>T	p.Thr640Met	missense	Exon 12 of 46	NP_001448.2	O75369-1
	FLNB	NM_001164317.2		c.1919C>T	p.Thr640Met	missense	Exon 12 of 47	NP_001157789.1	O75369-8
	FLNB	NM_001164318.2		c.1919C>T	p.Thr640Met	missense	Exon 12 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.1919C>T	p.Thr640Met	missense	Exon 12 of 46	ENSP00000295956.5	O75369-1
	FLNB	ENST00000490882.5	TSL:1	c.1919C>T	p.Thr640Met	missense	Exon 12 of 47	ENSP00000420213.1	O75369-8
	FLNB	ENST00000429972.6	TSL:1	c.1919C>T	p.Thr640Met	missense	Exon 12 of 46	ENSP00000415599.2	O75369-9

Frequencies

GnomAD3 genomes AF: 0.00864 AC: 1315 AN: 152156 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00261 AC: 654 AN: 250730 AF XY: 0.00199

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00124 AC: 1813 AN: 1461534 Hom.: 36 Cov.: 32 AF XY: 0.00114 AC XY: 831 AN XY: 727076

African (AFR) AF: 0.0341 AC: 1142 AN: 33470

American (AMR) AF: 0.00418 AC: 187 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00287 AC: 16 AN: 5572

European-Non Finnish (NFE) AF: 0.000238 AC: 265 AN: 1111926

Other (OTH) AF: 0.00311 AC: 188 AN: 60372

GnomAD4 genome AF: 0.00868 AC: 1322 AN: 152274 Hom.: 22 Cov.: 32 AF XY: 0.00851 AC XY: 634 AN XY: 74460

African (AFR) AF: 0.0302 AC: 1255 AN: 41536

American (AMR) AF: 0.00242 AC: 37 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

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

Alfa AF: 0.00367 Hom.: 15

Bravo AF: 0.0103

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00289 AC: 351

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.27
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.64	P
Vest4		0.32
MVP		0.93
MPC		0.47
ClinPred		0.023	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.18
Mutation Taster		=99/1	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: rs62621999; hg19: chr3-58092578;