rs3734972

Positions:

• chr7-128830784-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001458.5(FLNC):​c.147C>T​(p.His49His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 1,612,946 control chromosomes in the GnomAD database, including 6,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (714 hom., cov: 33)
  • Exomes 𝑓: 0.088 (5983 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.787

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 7-128830784-C-T is Benign according to our data. Variant chr7-128830784-C-T is described in ClinVar as [Benign]. Clinvar id is 129081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128830784-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.787 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.147C>T	p.His49His	synonymous_variant	1/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.147C>T	p.His49His	synonymous_variant	1/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.147C>T	p.His49His	synonymous_variant	1/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.147C>T	p.His49His	synonymous_variant	1/47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14287 AN: 152184 Hom.: 712 Cov.: 33

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.0985

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0982

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.0940 AC: 23381 AN: 248698 Hom.: 1163 AF XY: 0.0929 AC XY: 12551 AN XY: 135038

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0866

Gnomad ASJ exome AF: 0.0908

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.0847

Gnomad FIN exome AF: 0.0835

Gnomad NFE exome AF: 0.0861

Gnomad OTH exome AF: 0.0943

GnomAD4 exome AF: 0.0884 AC: 129166 AN: 1460644 Hom.: 5983 Cov.: 33 AF XY: 0.0887 AC XY: 64470 AN XY: 726626

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.0898

Gnomad4 ASJ exome AF: 0.0908

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.0876

Gnomad4 FIN exome AF: 0.0829

Gnomad4 NFE exome AF: 0.0848

Gnomad4 OTH exome AF: 0.0902

GnomAD4 genome AF: 0.0939 AC: 14307 AN: 152302 Hom.: 714 Cov.: 33 AF XY: 0.0939 AC XY: 6995 AN XY: 74478

Gnomad4 AFR AF: 0.0976

Gnomad4 AMR AF: 0.0881

Gnomad4 ASJ AF: 0.0985

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.0979

Gnomad4 FIN AF: 0.0844

Gnomad4 NFE AF: 0.0865

Gnomad4 OTH AF: 0.108

Alfa AF: 0.0883 Hom.: 789

Bravo AF: 0.0949

Asia WGS AF: 0.145 AC: 506 AN: 3478

EpiCase AF: 0.0921

EpiControl AF: 0.0885

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.His49His in exon 1 of FLNC: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 11.1% (487/4404) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs3734972). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 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 04, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.7
DANN	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3734972; hg19: chr7-128470838; COSMIC: COSV57952752;