rs28935169

Positions:

• chrX-154371001-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001110556.2(FLNA):​c.245A>T​(p.Glu82Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.76

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.

• PM1: In a domain Calponin-homology (CH) 1 (size 106) in uniprot entity FLNA_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001110556.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNA. . Gene score misZ 3.7802 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked Ehlers-Danlos syndrome, terminal osseous dysplasia-pigmentary defects syndrome, FG syndrome 2, frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, otopalatodigital syndrome type 2, periventricular nodular heterotopia, otopalatodigital syndrome type 1, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, familial thoracic aortic aneurysm and aortic dissection, congenital short bowel syndrome, frontometaphyseal dysplasia 1, cardiac valvular dysplasia, X-linked.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-154371001-T-A is Pathogenic according to our data. Variant chrX-154371001-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 11754.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154371001-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.245A>T	p.Glu82Val	missense_variant	2/48	ENST00000369850.10
FLNA	NM_001456.4	c.245A>T	p.Glu82Val	missense_variant	2/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.245A>T	p.Glu82Val	missense_variant	2/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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

Invitae

Apr 07, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FLNA function (PMID: 30224736). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FLNA protein function. ClinVar contains an entry for this variant (Variation ID: 11754). This missense change has been observed in individual(s) with periventricular heterotopia (PMID: 11914408; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 82 of the FLNA protein (p.Glu82Val). -

Heterotopia, periventricular, X-linked dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 26, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	28
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;H;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D;.;D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.041	B;.;B;B;.
Vest4		0.92
MutPred		0.92		Gain of MoRF binding (P = 0.0231);.;Gain of MoRF binding (P = 0.0231);Gain of MoRF binding (P = 0.0231);.;
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.97
gMVP		0.99

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: rs28935169; hg19: chrX-153599369;