chrX-154360233-C-T

Variant names:

• chrX-154360233-C-T
• rs28935472
• NM_001110556.2:c.3562G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001110556.2(FLNA):​c.3562G>A​(p.Ala1188Thr) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1188A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 25)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.82
• Publications: 13 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-154360233-C-T is Pathogenic according to our data. Variant chrX-154360233-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11758.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.3562G>A	p.Ala1188Thr	missense_variant	Exon 22 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.3562G>A	p.Ala1188Thr	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.3562G>A	p.Ala1188Thr	missense_variant	Exon 22 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 25

Alfa AF: 0.00216 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melnick-Needles syndrome Pathogenic:3 Other:1

Jan 04, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 05, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PP3, PP5 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Medical Genetics, Christian Medical College

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed variant has previously been reported in patients affected with Melnick-Needles syndrome and lies in the "Filamin/ABP280 repeat" domain of the FLNA protein (PF00630). The observed variation has been classified as pathogenic by the ClinVar database [VCV000011758.10]. -

not provided Pathogenic:2

Sep 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21228480, 27193221, 29575627, 12612583) -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLNA: PP4:Strong, PM1, PM2, PS4:Moderate, PP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;.;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.1	M;.;M;M;.
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D;.;D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.023	D;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.92
MutPred		0.85		Gain of disorder (P = 0.1602);.;Gain of disorder (P = 0.1602);Gain of disorder (P = 0.1602);.;
MVP		0.98
MPC		1.4
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.83
gMVP		0.69
Mutation Taster		=4/96	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: rs28935472; hg19: chrX-153588601; COSMIC: COSV61036943; COSMIC: COSV61036943;