chrX-154353628-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_001110556.2(FLNA):c.5786C>T(p.Pro1929Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,210,271 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1929S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000018 ( 0 hom. 6 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 9.89

Publications

1 publications found

Variant links:

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

FLNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

BS2

High Hemizygotes in GnomAdExome4 at 6 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.5786C>T	p.Pro1929Leu	missense_variant	Exon 36 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4 link	c.5762C>T	p.Pro1921Leu	missense_variant	Exon 35 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 link	c.5786C>T	p.Pro1929Leu	missense_variant	Exon 36 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

113029

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000321

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000165

AC:

AN:

181605

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000732

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1097242

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

362824

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26386

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

841617

Other (OTH)

AF:

0.00

AC:

AN:

46067

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000885

AC:

AN:

113029

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

35157

show subpopulations

African (AFR)

AF:

0.0000321

AC:

AN:

31152

American (AMR)

AF:

0.00

AC:

AN:

10775

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3607

South Asian (SAS)

AF:

0.00

AC:

AN:

2810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53281

Other (OTH)

AF:

0.00

AC:

AN:

1530

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Oct 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5762C>T (p.P1921L) alteration is located in exon 35 (coding exon 34) of the FLNA gene. This alteration results from a C to T substitution at nucleotide position 5762, causing the proline (P) at amino acid position 1921 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

FG syndrome 2

Uncertain:1

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3C. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease, where loss of function variants result in recessive disease and gain of function variants cause dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine (exon 36). (N) 0253 - Variant is hemizygous. (N) 0302 - Variant is present in gnomAD <0.001 (2 heterozygotes,1 hemizgyote, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygotes, 0 hemizygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif, (Filamin repeat; PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant has previously been described as variant of uncertain significance (ClinVar). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided

Uncertain:1

Apr 12, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 570943; Landrum et al., 2016) -

FLNA-related disorder

Uncertain:1

Jan 23, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FLNA c.5786C>T variant is predicted to result in the amino acid substitution p.Pro1929Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0073% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-153581996-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Benign:1

Jul 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.;.;.;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.8

H;.;.;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-9.3

D;.;D;D;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

D;.;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.87

MVP

0.99

MPC

1.4

ClinPred

1.0

GERP RS

4.4

PromoterAI

0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.89

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over