rs117366477

chr7-128845222-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):c.3757G>A(p.Val1253Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,613,764 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (8 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.111

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNC
• BP4: Computational evidence support a benign effect (MetaRNN=0.0046679676).
• BP6: Variant 7-128845222-G-A is Benign according to our data. Variant chr7-128845222-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128845222-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000722 (110/152304) while in subpopulation EAS AF= 0.0154 (80/5182). AF 95% confidence interval is 0.0127. There are 1 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.3757G>A	p.Val1253Ile	missense_variant	21/48	ENST00000325888.13
FLNC	NM_001127487.2	c.3757G>A	p.Val1253Ile	missense_variant	21/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.3757G>A	p.Val1253Ile	missense_variant	21/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.3757G>A	p.Val1253Ile	missense_variant	21/47	1		A1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00135 AC: 333 AN: 246900 Hom.: 4 AF XY: 0.00139 AC XY: 187 AN XY: 134250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.0149

Gnomad SAS exome AF: 0.000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000812

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000513 AC: 750 AN: 1461460 Hom.: 8 Cov.: 34 AF XY: 0.000532 AC XY: 387 AN XY: 727032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.0126

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0154

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000696 Hom.: 3

Bravo AF: 0.000808

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00123 AC: 149

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 03, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	7.9
Dann	Benign	0.92
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.18
Sift	Benign	0.42	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0060	B;B
Vest4		0.11
MVP		0.27
MPC		0.23
ClinPred		0.0030	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.013
gMVP		0.22

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: rs117366477; hg19: chr7-128485276;