rs80338840

Positions:

• chrX-154371177-CGT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001110556.2(FLNA):​c.67_68del​(p.Thr23AlafsTer82) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T23T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 25)
• Consequence: FLNA NM_001110556.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.11

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 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 168 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154371177-CGT-C is Pathogenic according to our data. Variant chrX-154371177-CGT-C is described in ClinVar as [Pathogenic]. Clinvar id is 11771.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154371177-CGT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.67_68del	p.Thr23AlafsTer82	frameshift_variant	2/48	ENST00000369850.10
FLNA	NM_001456.4	c.67_68del	p.Thr23AlafsTer82	frameshift_variant	2/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.67_68del	p.Thr23AlafsTer82	frameshift_variant	2/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 25

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

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

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: rs80338840; hg19: chrX-153599545;