chr1-15777220-A-T

Variant names:

• chr1-15777220-A-T
• rs1266233612
• NM_017556.4:c.941A>T

Variant summary

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

The NM_017556.4(FBLIM1):​c.941A>T​(p.Asp314Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FBLIM1 NM_017556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.78
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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.941A>T	p.Asp314Val	missense	Exon 8 of 9	NP_060026.2	Q8WUP2-1
	FBLIM1	NM_001350151.2		c.941A>T	p.Asp314Val	missense	Exon 9 of 10	NP_001337080.1	Q8WUP2-1
	FBLIM1	NM_001024216.3		c.650A>T	p.Asp217Val	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.941A>T	p.Asp314Val	missense	Exon 8 of 9	ENSP00000364921.3	Q8WUP2-1
	FBLIM1	ENST00000375771.5	TSL:1	c.941A>T	p.Asp314Val	missense	Exon 9 of 10	ENSP00000364926.1	Q8WUP2-1
	FBLIM1	ENST00000915887.1		c.1013A>T	p.Asp338Val	missense	Exon 9 of 10	ENSP00000585946.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251244 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460940 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726658

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111316

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.035	D
Polyphen		0.99	D
Vest4		0.41
MutPred		0.59		Loss of solvent accessibility (P = 0.0544)
MVP		0.86
ClinPred		0.82	D
GERP RS		4.9
Varity_R		0.39
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs1266233612; hg19: chr1-16103715;