1-15774945-G-C

Variant names:

• chr1-15774945-G-C
• rs376011206
• ENST00000441801.6:c.1039G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001024215.1(FBLIM1):​c.1039G>C​(p.Ala347Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,371,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 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. A347T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: FBLIM1 NM_001024215.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07690379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLIM1	NM_017556.4	c.890+149G>C		intron_variant	Intron 7 of 8	ENST00000375766.8	NP_060026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLIM1	ENST00000441801.6	c.1039G>C	p.Ala347Pro	missense_variant	Exon 6 of 6	1		ENSP00000416387.2
FBLIM1	ENST00000375766.8	c.890+149G>C		intron_variant	Intron 7 of 8	2	NM_017556.4	ENSP00000364921.3
FBLIM1	ENST00000375771.5	c.890+149G>C		intron_variant	Intron 8 of 9	1		ENSP00000364926.1
FBLIM1	ENST00000332305.5	c.599+149G>C		intron_variant	Intron 3 of 4	2		ENSP00000364920.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000715 AC: 1 AN: 139808 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1371472 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 674416

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: 0.00000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.17
DANN	Benign	0.97
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	4.3	N
REVEL	Benign	0.032
Sift	Benign	0.10	T
Sift4G	Benign	0.24	T
Polyphen		0.20	B
Vest4		0.19
MutPred		0.53		Loss of catalytic residue at A347 (P = 0.0474);
MVP		0.12
MPC		0.46
ClinPred		0.060	T
GERP RS		-1.1
gMVP		0.42

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

Other links and lift over

dbSNP: rs376011206; hg19: chr1-16101440;