7-128846080-A-T

Variant names:

• chr7-128846080-A-T
• rs944103680
• NM_001458.5:c.3881A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001458.5(FLNC):​c.3881A>T​(p.Asn1294Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1294S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.82

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.3881A>T	p.Asn1294Ile	missense_variant	Exon 22 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.3881A>T	p.Asn1294Ile	missense_variant	Exon 22 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.3881A>T	p.Asn1294Ile	missense_variant	Exon 22 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.3881A>T	p.Asn1294Ile	missense_variant	Exon 22 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461702 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000896

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 AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FLNC c.3881A>T (p.Asn1294Ile) results in a non-conservative amino acid change located in the Filamin/ABP280 repeat profile domain (IPR017868) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248978 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3881A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 944815). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Nov 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1294I variant (also known as c.3881A>T), located in coding exon 22 of the FLNC gene, results from an A to T substitution at nucleotide position 3881. The asparagine at codon 1294 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Uncertain:1

Jun 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1294 of the FLNC protein (p.Asn1294Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 944815). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.98	D;D
Vest4		0.79
MutPred		0.53		Loss of catalytic residue at N1294 (P = 0.0254);Loss of catalytic residue at N1294 (P = 0.0254);
MVP		0.84
MPC		1.0
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.50
gMVP		0.79

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: rs944103680; hg19: chr7-128486134;