rs201957008

Positions:

• chr7-128849174-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.4928-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,613,030 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (29 hom.)
• Consequence: FLNC NM_001458.5 splice_region, intron
• Scores: Splicing: ADA: 0.0006551
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.505

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 7-128849174-T-C is Benign according to our data. Variant chr7-128849174-T-C is described in ClinVar as [Benign]. Clinvar id is 196167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128849174-T-C is described in Lovd as [Benign]. Variant chr7-128849174-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00302 (459/151984) while in subpopulation SAS AF= 0.00894 (43/4808). AF 95% confidence interval is 0.00682. There are 1 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 459 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.4928-7T>C		splice_region_variant, intron_variant		ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.4928-7T>C		splice_region_variant, intron_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.4928-7T>C		splice_region_variant, intron_variant		1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.4928-7T>C		splice_region_variant, intron_variant		1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 458 AN: 151862 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00873

Gnomad FIN AF: 0.000570

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00493

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00428 AC: 1063 AN: 248080 Hom.: 7 AF XY: 0.00483 AC XY: 650 AN XY: 134700

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.00477 AC: 6975 AN: 1461046 Hom.: 29 Cov.: 37 AF XY: 0.00506 AC XY: 3679 AN XY: 726824

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.000806

Gnomad4 NFE exome AF: 0.00508

Gnomad4 OTH exome AF: 0.00322

GnomAD4 genome AF: 0.00302 AC: 459 AN: 151984 Hom.: 1 Cov.: 33 AF XY: 0.00283 AC XY: 210 AN XY: 74318

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000390

Gnomad4 SAS AF: 0.00894

Gnomad4 FIN AF: 0.000570

Gnomad4 NFE AF: 0.00493

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00396 Hom.: 2

Bravo AF: 0.00267

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00445

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2017	c.4928-7T>C in intron 28 of FLNC: This variant is not expected to have clinical significance because it has been identified in 1.1% (185/16270) of South Asian c hromosomes, including 1 homozygote by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs201957008). -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FLNC: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 24, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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	-0.49
CADD	Benign	14
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00066
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs201957008; hg19: chr7-128489228;