rs118124743

Positions:

• chr7-128852819-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001458.5(FLNC):​c.6005-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,613,792 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (169 hom.)
• Consequence: FLNC NM_001458.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0007572
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.181

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-128852819-T-C is Benign according to our data. Variant chr7-128852819-T-C is described in ClinVar as [Benign]. Clinvar id is 197000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128852819-T-C is described in Lovd as [Benign]. Variant chr7-128852819-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.6005-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000325888.13	NP_001449.3
FLNC-AS1	NR_149055.1	n.215+466A>G		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.5906-9T>C		splice_polypyrimidine_tract_variant, intron_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.6005-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001458.5	ENSP00000327145	P3
FLNC	ENST00000346177.6	c.5906-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000344002	A1
FLNC-AS1	ENST00000469965.1	n.215+466A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152166 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.0583

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00822 AC: 2050 AN: 249370 Hom.: 64 AF XY: 0.00996 AC XY: 1348 AN XY: 135356

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0173

Gnomad SAS exome AF: 0.0503

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00507 AC: 7410 AN: 1461508 Hom.: 169 Cov.: 33 AF XY: 0.00629 AC XY: 4576 AN XY: 727068

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0189

Gnomad4 SAS exome AF: 0.0499

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.00340 AC: 518 AN: 152284 Hom.: 12 Cov.: 33 AF XY: 0.00463 AC XY: 345 AN XY: 74452

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0203

Gnomad4 SAS AF: 0.0575

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00171

Asia WGS AF: 0.0400 AC: 140 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 16, 2023

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00076
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.060		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: rs118124743; hg19: chr7-128492873;