rs3734973

Variant names:

• chr7-128844762-A-G
• rs3734973
• NM_001458.5:c.3297A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001458.5(FLNC):​c.3297A>G​(p.Val1099Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,613,820 control chromosomes in the GnomAD database, including 38,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1099V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (8463 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30386 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.527
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen, Ambry Genetics
• myofibrillar myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• distal myopathy with posterior leg and anterior hand involvement

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-128844762-A-G is Benign according to our data. Variant chr7-128844762-A-G is described in ClinVar as Benign. ClinVar VariationId is 129084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.527 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001458.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.3297A>G	p.Val1099Val	synonymous	Exon 21 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.3297A>G	p.Val1099Val	synonymous	Exon 21 of 47	NP_001120959.1	Q14315-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.3297A>G	p.Val1099Val	synonymous	Exon 21 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.3297A>G	p.Val1099Val	synonymous	Exon 21 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.3294A>G	p.Val1098Val	synonymous	Exon 21 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43109 AN: 152070 Hom.: 8435 Cov.: 33

Gnomad AFR AF: 0.548

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.225 AC: 56011 AN: 249332 AF XY: 0.218

Gnomad AFR exome AF: 0.553

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.187 AC: 273588 AN: 1461632 Hom.: 30386 Cov.: 36 AF XY: 0.188 AC XY: 136465 AN XY: 727126

African (AFR) AF: 0.556 AC: 18602 AN: 33480

American (AMR) AF: 0.209 AC: 9347 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3322 AN: 26136

East Asian (EAS) AF: 0.464 AC: 18413 AN: 39700

South Asian (SAS) AF: 0.257 AC: 22144 AN: 86258

European-Finnish (FIN) AF: 0.141 AC: 7505 AN: 53202

Middle Eastern (MID) AF: 0.137 AC: 793 AN: 5768

European-Non Finnish (NFE) AF: 0.163 AC: 180985 AN: 1111976

Other (OTH) AF: 0.207 AC: 12477 AN: 60390

GnomAD4 genome AF: 0.284 AC: 43175 AN: 152188 Hom.: 8463 Cov.: 33 AF XY: 0.280 AC XY: 20842 AN XY: 74416

African (AFR) AF: 0.548 AC: 22749 AN: 41504

American (AMR) AF: 0.187 AC: 2855 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3468

East Asian (EAS) AF: 0.468 AC: 2419 AN: 5166

South Asian (SAS) AF: 0.281 AC: 1359 AN: 4830

European-Finnish (FIN) AF: 0.130 AC: 1379 AN: 10620

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11288 AN: 67996

Other (OTH) AF: 0.256 AC: 540 AN: 2106

Alfa AF: 0.207 Hom.: 5090

Bravo AF: 0.300

Asia WGS AF: 0.385 AC: 1335 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.162

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.3
DANN	Benign	0.67
PhyloP100		0.53
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3734973; hg19: chr7-128484816; COSMIC: COSV57950410; COSMIC: COSV57950410;