rs137853312

Positions:

• chrX-154360238-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_001110556.2(FLNA):​c.3557C>T​(p.Ser1186Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000879 in 113,783 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 25)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.90

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.

• 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.
• PP5: Variant X-154360238-G-A is Pathogenic according to our data. Variant chrX-154360238-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360238-G-A is described in Lovd as [Pathogenic]. Variant chrX-154360238-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.3557C>T	p.Ser1186Leu	missense_variant	22/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.3557C>T	p.Ser1186Leu	missense_variant	22/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.3557C>T	p.Ser1186Leu	missense_variant	22/48	1	NM_001110556.2	ENSP00000358866

Frequencies

GnomAD3 genomes AF: 0.00000879 AC: 1 AN: 113783 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 35917

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000879 AC: 1 AN: 113783 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 35917

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000187

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontometaphyseal dysplasia 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Claritas Genomics	Dec 07, 2009	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2006	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011761, PMID:12612583). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16835913, 16596676). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.709>=0.6). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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 08, 2018

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individuals affected with frontometaphyseal dysplasia (PMID: 16835913, 15523633, 16596676). In at least one of these individuals the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 11761). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 1186 of the FLNA protein (p.Ser1186Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2015

The S1186L variant in the FLNA gene has been reported previously in at least three unrelated male probands with frontometaphyseal dysplasia (Robertson et al., 2003; Giuliano et al., 2005; Zenker et al., 2006). The mothers of two of the probands shared the features of prominent brow and hypertelorism, and were less severely affected than their sons, presumably due to skewed X-inactivation (Giuliano et al., 2005; Zenker et al., 2006). The S1186L variant is noted to segregate only with a FMD presentation in contrast to other FLNA variants where the same variant may present with different FLNA-related phenotypes (Zenker et al., 2006). The S1186L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1186L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Serine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D1184E, A1188T) have been reported in the Human Gene Mutation Database in association with Melnick-Needles syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The S1186L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	2.9	M;.;M;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.9	D;.;D;D;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.012	D;.;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.40	B;.;D;D;.
Vest4		0.50
MutPred		0.69		Loss of disorder (P = 0.0239);.;Loss of disorder (P = 0.0239);Loss of disorder (P = 0.0239);.;
MVP		0.96
MPC		1.2
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.76
gMVP		0.37

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: rs137853312; hg19: chrX-153588606;