chr1-15777183-G-C

Variant names:

• chr1-15777183-G-C
• rs138158787
• NM_017556.4:c.904G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017556.4(FBLIM1):​c.904G>C​(p.Val302Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 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. V302I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBLIM1 NM_017556.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.253
• Publications: 1 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]

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

ACMG classification

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=0.10239431).

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.904G>C	p.Val302Leu	missense	Exon 8 of 9	NP_060026.2	Q8WUP2-1
	FBLIM1	NM_001350151.2		c.904G>C	p.Val302Leu	missense	Exon 9 of 10	NP_001337080.1	Q8WUP2-1
	FBLIM1	NM_001024216.3		c.613G>C	p.Val205Leu	missense	Exon 6 of 7	NP_001019387.1	Q8WUP2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLIM1	ENST00000375766.8	TSL:2 MANE Select	c.904G>C	p.Val302Leu	missense	Exon 8 of 9	ENSP00000364921.3	Q8WUP2-1
	FBLIM1	ENST00000375771.5	TSL:1	c.904G>C	p.Val302Leu	missense	Exon 9 of 10	ENSP00000364926.1	Q8WUP2-1
	FBLIM1	ENST00000915887.1		c.976G>C	p.Val326Leu	missense	Exon 9 of 10	ENSP00000585946.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250528 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454194 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721776

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.00 AC: 0 AN: 85930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105806

Other (OTH) AF: 0.00 AC: 0 AN: 60024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.59
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.25
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.14
Sift	Benign	0.60	T
Sift4G	Benign	0.63	T
Polyphen		0.0020	B
Vest4		0.26
MutPred		0.49		Loss of ubiquitination at K298 (P = 0.1601)
MVP		0.46
ClinPred		0.048	T
GERP RS		-0.28
Varity_R		0.036
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs138158787; hg19: chr1-16103678;