rs137853317

Variant names:

• chrX-154367878-G-A
• rs137853317
• NM_001110556.2:c.586C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 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. R196G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications 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 16 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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 rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.586C>T	p.Arg196Trp	missense_variant	Exon 3 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.586C>T	p.Arg196Trp	missense_variant	Exon 3 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.586C>T	p.Arg196Trp	missense_variant	Exon 3 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 28, 2008

Claritas Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:1

Jan 21, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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

Jan 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
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;