Genetic Variant FBLIM1:p.Met78Lys (chr1-15765216-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017556.4(FBLIM1):c.233T>A(p.Met78Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M78T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBLIM1
NM_017556.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0600

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.071846485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLIM1	NM_017556.4 link	c.233T>A	p.Met78Lys	missense_variant	Exon 3 of 9	ENST00000375766.8	NP_060026.2	Q8WUP2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLIM1	ENST00000375766.8 link	c.233T>A	p.Met78Lys	missense_variant	Exon 3 of 9	2	NM_017556.4	ENSP00000364921.3		Q8WUP2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460486

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726414

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.7

DANN

Benign

0.71

DEOGEN2

Benign

0.020

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

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.61

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

M_CAP

Benign

0.0081

MetaRNN

Benign

0.072

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N;.;.;.;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.054

Sift

Uncertain

0.013

D;T;T;D;T;D;T;T

Sift4G

Uncertain

0.0050

D;T;T;T;T;T;T;T

Polyphen

0.0010, 0.0

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

Vest4

0.12, 0.12, 0.14

MutPred

0.40

Gain of ubiquitination at M78 (P = 0.0094);Gain of ubiquitination at M78 (P = 0.0094);Gain of ubiquitination at M78 (P = 0.0094);Gain of ubiquitination at M78 (P = 0.0094);Gain of ubiquitination at M78 (P = 0.0094);Gain of ubiquitination at M78 (P = 0.0094);Gain of ubiquitination at M78 (P = 0.0094);Gain of ubiquitination at M78 (P = 0.0094);

MVP

0.12

MPC

0.35

ClinPred

0.020

GERP RS

-0.61

Varity_R

0.22

gMVP

0.20

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over