rs137853317

Positions:

• chrX-154367878-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001110556.2(FLNA):​c.586C>T​(p.Arg196Trp) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 0.992

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 17 ACMG points.

• PM1: In a helix (size 9) in uniprot entity FLNA_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001110556.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.857
• PP5: Variant X-154367878-G-A is Pathogenic according to our data. Variant chrX-154367878-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154367878-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.586C>T	p.Arg196Trp	missense_variant	3/48	ENST00000369850.10
FLNA	NM_001456.4	c.586C>T	p.Arg196Trp	missense_variant	3/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.586C>T	p.Arg196Trp	missense_variant	3/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oto-palato-digital syndrome, type I Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Claritas Genomics	Feb 28, 2008	- -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33767182, 12612583, 17264970, 37010288) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2014	- -

Oto-palato-digital syndrome, type II Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

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

Jun 13, 2022

For these reasons, this variant has been classified as Pathogenic. 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: 11772). This missense change has been observed in individuals with clinical features of FLNA-related conditions (PMID: 12612583, 15194946, 17264970; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 196 of the FLNA protein (p.Arg196Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	23
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.95	D;.;.;.;.
FATHMM_MKL	Benign	0.50	N
LIST_S2	Pathogenic	0.99	D;D;.;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.8	M;.;M;M;.
MutationTaster	Benign	0.98	A;A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.5	D;.;D;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.57
MutPred		0.81		Loss of disorder (P = 0.0809);.;Loss of disorder (P = 0.0809);Loss of disorder (P = 0.0809);.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.93
gMVP		0.94

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: rs137853317; hg19: chrX-153596246; COSMIC: COSV61047511; COSMIC: COSV61047511;