7-128848058-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001458.5(FLNC):c.4570G>T(p.Val1524Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V1524M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08

Genes affected

FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FLNC

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.4570G>T	p.Val1524Leu	missense_variant	26/48	ENST00000325888.13
FLNC	NM_001127487.2	c.4570G>T	p.Val1524Leu	missense_variant	26/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.4570G>T	p.Val1524Leu	missense_variant	26/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.4570G>T	p.Val1524Leu	missense_variant	26/47	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452122 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 721514

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.093	T;T
Polyphen		0.83	P;D
Vest4		0.68
MutPred		0.63		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.56
MPC		0.96
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.48

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: rs1358403336; hg19: chr7-128488112;