chr7-128830439-A-G

Position:

• chr7-128830439-A-G

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.-199A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00863 in 595,076 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (20 hom.)
• Consequence: FLNC NM_001458.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.151

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=-0.53).
• BP6: Variant 7-128830439-A-G is Benign according to our data. Variant chr7-128830439-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1207031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00813 (1232/151606) while in subpopulation AMR AF= 0.00943 (144/15272). AF 95% confidence interval is 0.00839. There are 9 homozygotes in gnomad4. There are 663 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1232 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.-199A>G		5_prime_UTR_variant	1/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.-199A>G		5_prime_UTR_variant	1/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888	c.-199A>G		5_prime_UTR_variant	1/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177	c.-199A>G		5_prime_UTR_variant	1/47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1232 AN: 151492 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00944

Gnomad ASJ AF: 0.00781

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00898

Gnomad OTH AF: 0.0111

GnomAD4 exome AF: 0.00880 AC: 3904 AN: 443470 Hom.: 20 Cov.: 3 AF XY: 0.00846 AC XY: 1988 AN XY: 235080

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00638

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.0000677

Gnomad4 SAS exome AF: 0.00257

Gnomad4 FIN exome AF: 0.0317

Gnomad4 NFE exome AF: 0.00891

Gnomad4 OTH exome AF: 0.00799

GnomAD4 genome AF: 0.00813 AC: 1232 AN: 151606 Hom.: 9 Cov.: 33 AF XY: 0.00895 AC XY: 663 AN XY: 74104

Gnomad4 AFR AF: 0.00160

Gnomad4 AMR AF: 0.00943

Gnomad4 ASJ AF: 0.00781

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.0341

Gnomad4 NFE AF: 0.00898

Gnomad4 OTH AF: 0.0110

Alfa AF: 0.00400 Hom.: 2

Bravo AF: 0.00638

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.75

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: rs572932306; hg19: chr7-128470493;