rs114713626

Positions:

• chr7-128858524-A-G

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.*1A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,610,990 control chromosomes in the GnomAD database, including 1,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (593 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (429 hom.)
• Consequence: FLNC NM_001458.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.997

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=-0.59).
• BP6: Variant 7-128858524-A-G is Benign according to our data. Variant chr7-128858524-A-G is described in ClinVar as [Benign]. Clinvar id is 258124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128858524-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.*1A>G		3_prime_UTR_variant	48/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.102+4001T>C		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.*1A>G		3_prime_UTR_variant	47/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.*1A>G		3_prime_UTR_variant	48/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.*1A>G		3_prime_UTR_variant	47/47	1		A1
FLNC-AS1	ENST00000469965.1	n.102+4001T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7211 AN: 151930 Hom.: 592 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.0345

GnomAD3 exomes AF: 0.0124 AC: 3091 AN: 248770 Hom.: 205 AF XY: 0.0101 AC XY: 1370 AN XY: 135040

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.00795

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.00455

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00612

GnomAD4 exome AF: 0.00603 AC: 8792 AN: 1458942 Hom.: 429 Cov.: 31 AF XY: 0.00556 AC XY: 4037 AN XY: 725934

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.00882

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.00477

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00208

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.0475 AC: 7220 AN: 152048 Hom.: 593 Cov.: 32 AF XY: 0.0455 AC XY: 3379 AN XY: 74338

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.0342

Alfa AF: 0.0243 Hom.: 111

Bravo AF: 0.0534

EpiCase AF: 0.00185

EpiControl AF: 0.00237

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 29, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 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	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+	-	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 09, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs114713626; hg19: chr7-128498578;