NM_001458.5:c.5579G>T

Variant names:

• chr7-128851271-G-T
• rs1019973830
• NM_001458.5:c.5579G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001458.5(FLNC):​c.5579G>T​(p.Arg1860Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1860H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96
• Publications: 1 publications found

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]

FLNC-AS1 (HGNC:53474): (FLNC antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2332604).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001458.5. 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
	FLNC	NM_001458.5	MANE Select	c.5579G>T	p.Arg1860Leu	missense	Exon 34 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.5480G>T	p.Arg1827Leu	missense	Exon 33 of 47	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.315+130C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.5579G>T	p.Arg1860Leu	missense	Exon 34 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.5480G>T	p.Arg1827Leu	missense	Exon 33 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.5477G>T	p.Arg1826Leu	missense	Exon 33 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249476 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: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461792 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		8.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.15
Sift	Benign	0.052	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.054	B
Vest4		0.48
MutPred		0.62		Loss of disorder (P = 0.0846)
MVP		0.27
MPC		1.5
ClinPred		0.89	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.28
gMVP		0.74
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs1019973830; hg19: chr7-128491325;