X-154348850-CAG-C

Position:

• chrX-154348850-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001110556.2(FLNA):​c.7941_7942del​(p.Ter2648SerfsTer101) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 frameshift, stop_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.22

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 18 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154348850-CAG-C is Pathogenic according to our data. Variant chrX-154348850-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154348850-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.7941_7942del	p.Ter2648SerfsTer101	frameshift_variant, stop_lost	48/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.7917_7918del	p.Ter2640SerfsTer101	frameshift_variant, stop_lost	47/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.7941_7942del	p.Ter2648SerfsTer101	frameshift_variant, stop_lost	48/48	1	NM_001110556.2	ENSP00000358866

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2023

This protein extension has been observed in individual(s) with bilateral periventricular heterotopia, congenital short bowel, and additional FLNA-related conditions (PMID: 23873601, 28428218). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this protein extension alters FLNA gene expression (PMID: 23873601, 28428218). ClinVar contains an entry for this variant (Variation ID: 213498). This variant is also known as c.7941_7942delCT (p.2648Serext*100). This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the FLNA mRNA. It is expected to extend the length of the FLNA protein by 100 additional amino acid residues. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Stop codon loss and change to a stop codon, leading to protein extension and the addition of 100 amino acids at the C-terminus in a gene for which protein extension is a known mechanism of disease; Also known as p.(Ter2648SerextTer101); This variant is associated with the following publications: (PMID: 28428218, 23873601) -

Heterotopia, periventricular, X-linked dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs863223636; hg19: chrX-153577218;