rs745488329

Variant names:

• chr7-128858227-G-A
• rs745488329
• NM_001458.5:c.7990+10G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128858227-G-A
• chr7-128858227-G-C
• chr7-128858227-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001458.5(FLNC):​c.7990+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 1,401,816 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0330
• Publications: 0 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-AS1 (HGNC:53474): (FLNC antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-128858227-G-A is Benign according to our data. Variant chr7-128858227-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 539492.

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.7990+10G>A		intron	N/A	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.7891+10G>A		intron	N/A	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.102+4298C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.7990+10G>A		intron	N/A	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.7891+10G>A		intron	N/A	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.7888+10G>A		intron	N/A	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151838 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000445 AC: 9 AN: 202442 AF XY: 0.0000181

Gnomad AFR exome AF: 0.000166

Gnomad AMR exome AF: 0.000105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000457

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000368 AC: 46 AN: 1249978 Hom.: 0 Cov.: 19 AF XY: 0.0000301 AC XY: 19 AN XY: 631428

African (AFR) AF: 0.000465 AC: 14 AN: 30120

American (AMR) AF: 0.0000690 AC: 3 AN: 43466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24622

East Asian (EAS) AF: 0.00 AC: 0 AN: 38520

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4530

European-Non Finnish (NFE) AF: 0.0000260 AC: 24 AN: 921694

Other (OTH) AF: 0.0000564 AC: 3 AN: 53168

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151838 Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7 AN XY: 74154

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000339 AC: 14 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67938

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000278793), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000480 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy (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	-0.86
CADD	Benign	8.0
DANN	Benign	0.74
PhyloP100		-0.033
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs745488329; hg19: chr7-128498281;