1-15765096-G-A

Position:

chr1-15765096-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017556.4(FBLIM1):c.113G>A(p.Arg38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,613,872 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0025 ( 22 hom. )

Consequence

FBLIM1
NM_017556.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.01

Variant links:

Genes affected

FBLIM1 (HGNC:24686): (filamin binding LIM protein 1) This gene encodes a protein with an N-terminal filamin-binding domain, a central proline-rich domain, and, multiple C-terminal LIM domains. This protein localizes at cell junctions and may link cell adhesion structures to the actin cytoskeleton. This protein may be involved in the assembly and stabilization of actin-filaments and likely plays a role in modulating cell adhesion, cell morphology and cell motility. This protein also localizes to the nucleus and may affect cardiomyocyte differentiation after binding with the CSX/NKX2-5 transcription factor. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FBLIM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025619268).

BP6

Variant 1-15765096-G-A is Benign according to our data. Variant chr1-15765096-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1722439.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLIM1	NM_017556.4 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	3/9	ENST00000375766.8	NP_060026.2	Q8WUP2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLIM1	ENST00000375766.8 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	3/9	2	NM_017556.4	ENSP00000364921.3		Q8WUP2-1

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

358

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00406

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00390

AC:

972

AN:

249050

Hom.:

AF XY:

0.00462

AC XY:

623

AN XY:

134834

show subpopulations

Gnomad AFR exome

AF:

0.000813

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00624

Gnomad SAS exome

AF:

0.0136

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00221

Gnomad OTH exome

AF:

0.00426

GnomAD4 exome

AF:

0.00250

AC:

3660

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

2139

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00957

Gnomad4 EAS exome

AF:

0.00542

Gnomad4 SAS exome

AF:

0.0127

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00152

Gnomad4 OTH exome

AF:

0.00371

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152318

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00407

Gnomad4 SAS

AF:

0.0114

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00241

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00281

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00414

AC:

502

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 08, 2022

Variant summary: FBLIM1 c.113G>A (p.Arg38Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0039 in 249050 control chromosomes in the gnomAD database, including 6 homozygotes. In addition, a study by Kars et al (2021) investigated the genetic structure of Turkey from 3,362 unrelated subjects and detected the variant in 18 homozygous individuals. c.113G>A has been reported in the literature in individuals affected with Chronic Osteomyelitis and developmental delay or intellectual disability (Cox_2017, dAdamo_2020, Hiraide_2021). These reports do not provide unequivocal conclusions about association of the variant with FBLIM1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

FBLIM1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

T;T;T;T;T;.;.;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.69

T;.;T;T;T;T;T;T

MetaRNN

Benign

0.0026

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;L;L;.;.;.;L;L

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N;N

REVEL

Benign

0.072

Sift

Benign

0.18

T;T;T;T;T;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T;T;T;T

Polyphen

0.018, 0.0030, 0.0010

.;B;B;.;.;.;B;B

Vest4

0.10, 0.10, 0.089, 0.064

MVP

0.48

MPC

0.26

ClinPred

0.0027

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.051

gMVP

0.091

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over