rs886038987

Variant names:

• chrX-154366826-ACCATGTTG-A
• rs886038987
• NM_001110556.2:c.885_892delCAACATGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001110556.2(FLNA):​c.885_892delCAACATGG​(p.Asn296GlufsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: FLNA NM_001110556.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.96

Genes affected

FLNA (HGNC:3754): (filamin A) The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154366826-ACCATGTTG-A is Pathogenic according to our data. Variant chrX-154366826-ACCATGTTG-A is described in ClinVar as [Pathogenic]. Clinvar id is 263954.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154366826-ACCATGTTG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.885_892delCAACATGG	p.Asn296GlufsTer38	frameshift_variant	Exon 6 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.885_892delCAACATGG	p.Asn296GlufsTer38	frameshift_variant	Exon 6 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.885_892delCAACATGG	p.Asn296GlufsTer38	frameshift_variant	Exon 6 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000557 AC: 1 AN: 179682 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097099 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 362587

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Apr 06, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.885_892delCAACATGG (p.N296Efs*38) pathogenic mutation, located in coding exon 5 of the FLNA gene, results from a deletion of 8 nucleotides between nucleotide positions 885 and 892, causing a translational frameshift with a predicted alternate stop codon. This mutation was observed in a proband and her daughter, both with periventricular heterotopia, loose-joints, and easy bruising. In addition, the proband had a history of an aortic aneurysm. The daughter previously had an an aneurysm of the proximal right subclavian artery. X-inactivation studies demonstrated random X inactivation and subsequent cultured fibroblasts had two cells lines in which one was observed to have no detectable FLNA protein (Reinstein E, Am. J. Med. Genet. A 2012 Aug; 158A(8):1897-901). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886038987; hg19: chrX-153595194;