rs766439553

Variant names:

• chr7-128844964-C-A
• NM_001458.5:c.3499C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128844964-C-A
• chr7-128844964-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001458.5(FLNC):​c.3499C>A​(p.Arg1167Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27682203).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.3499C>A	p.Arg1167Ser	missense_variant	Exon 21 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.3499C>A	p.Arg1167Ser	missense_variant	Exon 21 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.3499C>A	p.Arg1167Ser	missense_variant	Exon 21 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.3499C>A	p.Arg1167Ser	missense_variant	Exon 21 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461490 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727070

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3499C>A (p.R1167S) alteration is located in exon 21 (coding exon 21) of the FLNC gene. This alteration results from a C to A substitution at nucleotide position 3499, causing the arginine (R) at amino acid position 1167 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.45
Sift	Benign	0.096	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.034	B;P
Vest4		0.47
MutPred		0.44		Gain of glycosylation at R1167 (P = 0.0123);Gain of glycosylation at R1167 (P = 0.0123);
MVP		0.68
MPC		0.59
ClinPred		0.95	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.42
gMVP		0.44

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-128485018;