rs797044753

Positions:

• chrX-154367532-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001110556.2(FLNA):​c.733G>A​(p.Glu245Lys) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.85

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 10 ACMG points.

• PM1: In a domain Calponin-homology (CH) 2 (size 103) in uniprot entity FLNA_HUMAN there are 4 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, 0.951
• PP5: Variant X-154367532-C-T is Pathogenic according to our data. Variant chrX-154367532-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197727.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chrX-154367532-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.733G>A	p.Glu245Lys	missense_variant	5/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.733G>A	p.Glu245Lys	missense_variant	5/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.733G>A	p.Glu245Lys	missense_variant	5/48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Frontometaphyseal dysplasia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 11, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss of function is the mechanism of truncating or distal truncating, hypomorphic missense or mosaic variants which cause periventricular nodular heterotopia, X-linked cardiac valvular dystrophy and gastrointestinal diseases. Whereas, gain of function is the mechanism of most missense and small in-frame deletions cluster in ABD and filamin repeats 3, 10 and 14/15 domains that lead to Oto-palato-digital spectrum of disease. Lastly, X-linked cardiac valvular dystrophy is caused by mostly missense or splice in filamin repeats 1, 4, 5, 6 and 7 (PMID:30089473). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine (exon 5 of 48). (N) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (P) 0603 - Missense variant in the calponin homology domain that is highly intolerant to missense variation. (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in one patient with Frontometaphyseal Dysplasia (PMID: 16835913), it has also been reported once as a VUS in ClinVar. (P) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited (inheritance testing at the Broad institute). (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 245 of the FLNA protein (p.Glu245Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with FLNA-related conditions (PMID: 16835913; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197727). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNA protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 24, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;D;D;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.80
MutPred		0.80		Gain of methylation at E245 (P = 0.0062);.;Gain of methylation at E245 (P = 0.0062);Gain of methylation at E245 (P = 0.0062);.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs797044753; hg19: chrX-153595900;