1-15765006-G-A

Position:

• chr1-15765006-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017556.4(FBLIM1):​c.23G>A​(p.Arg8Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,388 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (1 hom.)
• Consequence: FBLIM1 NM_017556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBLIM1	NM_017556.4	c.23G>A	p.Arg8Lys	missense_variant	3/9	ENST00000375766.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLIM1	ENST00000375766.8	c.23G>A	p.Arg8Lys	missense_variant	3/9	2	NM_017556.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461388 Hom.: 1 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726966

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.23G>A (p.R8K) alteration is located in exon 2 (coding exon 1) of the FBLIM1 gene. This alteration results from a G to A substitution at nucleotide position 23, causing the arginine (R) at amino acid position 8 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;T;.;T;.;T;T;T;T;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;T;.;.;.;T;T;T;T;T;T;T
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.019	D
MutationAssessor	Benign	2.0	.;.;.;.;M;.;.;M;.;.;.;M;M
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D;D;D;D;N;D;D;N;D;N;D;N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	.;D;D;.;D;.;.;D;D;D;D;D;T
Sift4G	Pathogenic	0.0	D;D;D;.;D;.;D;D;T;T;D;T;T
Polyphen		0.99, 0.99, 0.89	.;.;.;.;D;.;.;D;.;.;.;D;P
Vest4		0.59, 0.59, 0.61, 0.44
MutPred		0.38		Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);Gain of methylation at R8 (P = 0.0087);
MVP		0.83
MPC		0.78
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.92
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs752828267; hg19: chr1-16091501;