rs794727437

chr7-128848722-GTC-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):c.4737+9_4737+10del variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,613,844 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (73 hom.)
• Consequence: FLNC NM_001458.5 splice_donor_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.24

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 -16 ACMG points.

• BP6: Variant 7-128848722-GTC-G is Benign according to our data. Variant chr7-128848722-GTC-G is described in ClinVar as [Benign]. Clinvar id is 196015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128848722-GTC-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00177 (269/152292) while in subpopulation SAS AF= 0.028 (135/4828). AF 95% confidence interval is 0.0241. There are 2 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 270 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.4737+9_4737+10del		splice_donor_region_variant, intron_variant		ENST00000325888.13
FLNC	NM_001127487.2	c.4737+9_4737+10del		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.4737+9_4737+10del		splice_donor_region_variant, intron_variant		1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.4737+9_4737+10del		splice_donor_region_variant, intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152174 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00420 AC: 1045 AN: 249072 Hom.: 19 AF XY: 0.00553 AC XY: 747 AN XY: 135178

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0273

Gnomad FIN exome AF: 0.0000473

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00285 AC: 4167 AN: 1461552 Hom.: 73 AF XY: 0.00353 AC XY: 2567 AN XY: 727106

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152292 Hom.: 2 Cov.: 33 AF XY: 0.00220 AC XY: 164 AN XY: 74450

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0280

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00105

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:6

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2016

- -

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs794727437; hg19: chr7-128488776;