rs1557175195

Positions:

• chrX-154349013-C-CCCCCGAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001110556.2(FLNA):​c.7779_7780insTTCGGGG​(p.Val2594PhefsTer158) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: FLNA NM_001110556.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -2.70

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0208 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154349013-C-CCCCCGAA is Pathogenic according to our data. Variant chrX-154349013-C-CCCCCGAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 453200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.7779_7780insTTCGGGG	p.Val2594PhefsTer158	frameshift_variant	48/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.7755_7756insTTCGGGG	p.Val2586PhefsTer158	frameshift_variant	47/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.7779_7780insTTCGGGG	p.Val2594PhefsTer158	frameshift_variant	48/48	1	NM_001110556.2	ENSP00000358866

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

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 24, 2019

For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the FLNA protein. Other variant(s) that result in a similarly extended protein product (p.Glu2617Valfs*124) have been determined to be pathogenic (Invitae). This suggests that these extensions are likely to be causative of disease. This variant has been observed to segregate with clinical features of FLNA-related disorders in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 453200). This variant is not present in population databases (ExAC no frequency). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acids of the FLNA protein and is expected to extend the length of the FLNA protein by 104 additional residues. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2017

Although the c.7755_7756insTTCGGGG variant in the FLNA gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon valine 2586, changing it to a phenylalanine, and replaces the last 54 amino acids with 157 incorrect amino acids, thus altering and extending the resulting protein product. Other frameshift variants in the FLNA gene that extend the protein have been reported in Human Gene Mutation Database in association with PH (Stenson et al., 2014). Furthermore, the c.7755_7756insTTCGGGG variant has not been observed in large population cohorts (Lek et al., 2016). -

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: rs1557175195; hg19: chrX-153577381;