chr1-15774637-G-A

Variant names:

• chr1-15774637-G-A
• NM_017556.4:c.731G>A

Variant summary

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

The NM_017556.4(FBLIM1):​c.731G>A​(p.Gly244Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G244S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: FBLIM1 NM_017556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

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 rank	MANE	Protein	UniProt
FBLIM1	NM_017556.4	c.731G>A	p.Gly244Asp	missense_variant	Exon 7 of 9	ENST00000375766.8	NP_060026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLIM1	ENST00000375766.8	c.731G>A	p.Gly244Asp	missense_variant	Exon 7 of 9	2	NM_017556.4	ENSP00000364921.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461386 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726996

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.731G>A (p.G244D) alteration is located in exon 6 (coding exon 5) of the FBLIM1 gene. This alteration results from a G to A substitution at nucleotide position 731, causing the glycine (G) at amino acid position 244 to be replaced by an aspartic acid (D). 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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.7	L;L;L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.18	T;T;D;T
Sift4G	Benign	0.068	T;T;D;T
Polyphen		0.97	D;D;D;D
Vest4		0.51
MutPred		0.47		Gain of solvent accessibility (P = 0.154);Gain of solvent accessibility (P = 0.154);Gain of solvent accessibility (P = 0.154);.;
MVP		0.93
MPC		0.86
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.17
gMVP		0.49

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.

Other links and lift over

hg19: chr1-16101132;