1-15765006-G-C

Variant names:

• chr1-15765006-G-C
• rs752828267
• NM_017556.4:c.23G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017556.4(FBLIM1):​c.23G>C​(p.Arg8Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R8K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBLIM1 NM_017556.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLIM1	NM_017556.4	MANE Select	c.23G>C	p.Arg8Thr	missense	Exon 3 of 9	NP_060026.2	Q8WUP2-1
	FBLIM1	NM_001024215.1		c.23G>C	p.Arg8Thr	missense	Exon 2 of 6	NP_001019386.1	Q8WUP2-2
	FBLIM1	NM_001350151.2		c.23G>C	p.Arg8Thr	missense	Exon 4 of 10	NP_001337080.1	Q8WUP2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLIM1	ENST00000375766.8	TSL:2 MANE Select	c.23G>C	p.Arg8Thr	missense	Exon 3 of 9	ENSP00000364921.3	Q8WUP2-1
	FBLIM1	ENST00000441801.6	TSL:1	c.23G>C	p.Arg8Thr	missense	Exon 2 of 6	ENSP00000416387.2	Q8WUP2-2
	FBLIM1	ENST00000375771.5	TSL:1	c.23G>C	p.Arg8Thr	missense	Exon 4 of 10	ENSP00000364926.1	Q8WUP2-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.44		Loss of MoRF binding (P = 5e-04)
MVP		0.90
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		0.00030	Neutral
Varity_R		0.92
gMVP		0.60
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752828267; hg19: chr1-16091501;