rs137853312

Variant names:

• chrX-154360238-G-A
• rs137853312
• NM_001110556.2:c.3557C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 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:6
• Conservation: PhyloP100: 9.90
• Publications: 10 publications found

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]

FLNA Gene-Disease associations (from GenCC):

• periventricular nodular heterotopia

  Inheritance: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• frontometaphyseal dysplasia 1

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• heterotopia, periventricular, X-linked dominant

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Melnick-Needles syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• otopalatodigital syndrome type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• terminal osseous dysplasia-pigmentary defects syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• cardiac valvular dysplasia, X-linked

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• frontometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital short bowel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• otopalatodigital syndrome type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Ehlers-Danlos syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154360238-G-A is Pathogenic according to our data. Variant chrX-154360238-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.3557C>T	p.Ser1186Leu	missense_variant	Exon 22 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

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

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31434

American (AMR) AF: 0.00 AC: 0 AN: 10911

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2663

East Asian (EAS) AF: 0.00 AC: 0 AN: 3612

South Asian (SAS) AF: 0.00 AC: 0 AN: 2868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53410

Other (OTH) AF: 0.00 AC: 0 AN: 1542

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000455 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontometaphyseal dysplasia 1 Pathogenic:2

Dec 07, 2009

Claritas Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1186 of the FLNA protein (p.Ser1186Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with frontometaphyseal dysplasia (PMID: 15523633, 16596676, 16835913). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11761). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FLNA protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Melnick-Needles syndrome;C0262436:Cardiac valvular dysplasia, X-linked;C0265251:Oto-palato-digital syndrome, type I;C1844696:Oto-palato-digital syndrome, type II;C1845902:FG syndrome 2;C1846129:Terminal osseous dysplasia-pigmentary defects syndrome;C1848213:Heterotopia, periventricular, X-linked dominant;C2746068:Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked;C4281559:Frontometaphyseal dysplasia 1 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS2_Supporting+PS4_Moderate+PP2+PP4 -

not provided Pathogenic:1

Nov 01, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		9.9
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137853312; hg19: chrX-153588606;