Genetic Variant NM_017556.4:c.970A>T (chr1-15777249-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017556.4(FBLIM1):c.970A>T(p.Met324Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,190 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. M324V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

FBLIM1
NM_017556.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.07

Publications

0 publications found

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:

SPEN-AS1 (HGNC:55937): (SPEN antisense RNA 1)

SPEN-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11701292).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017556.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBLIM1	NM_017556.4	MANE Select	c.970A>T	p.Met324Leu	missense	Exon 8 of 9	NP_060026.2	Q8WUP2-1
FBLIM1	NM_001350151.2		c.970A>T	p.Met324Leu	missense	Exon 9 of 10	NP_001337080.1	Q8WUP2-1
FBLIM1	NM_001024216.3		c.679A>T	p.Met227Leu	missense	Exon 6 of 7	NP_001019387.1	Q8WUP2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBLIM1	ENST00000375766.8	TSL:2 MANE Select	c.970A>T	p.Met324Leu	missense	Exon 8 of 9	ENSP00000364921.3	Q8WUP2-1
FBLIM1	ENST00000375771.5	TSL:1	c.970A>T	p.Met324Leu	missense	Exon 9 of 10	ENSP00000364926.1	Q8WUP2-1
FBLIM1	ENST00000915887.1		c.1042A>T	p.Met348Leu	missense	Exon 9 of 10	ENSP00000585946.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.0098

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.093

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

M_CAP

Benign

0.017

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.65

MutationAssessor

Benign

-0.54

PhyloP100

4.1

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.59

REVEL

Benign

0.26

Sift

Benign

0.89

Sift4G

Benign

1.0

Polyphen

0.053

Vest4

0.27

MutPred

0.64

Gain of catalytic residue at M324 (P = 0.0775)

MVP

0.61

ClinPred

0.66

GERP RS

4.9

Varity_R

0.14

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over