rs727503930

Positions:

chrX-154350192-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2

The NM_001110556.2(FLNA):c.7172G>A(p.Arg2391His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,210,274 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 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).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000084 ( 0 hom. 36 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 7.82

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 links:

FLNA (HGNC:):

FLNA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

BP6

Variant X-154350192-C-T is Benign according to our data. Variant chrX-154350192-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167077.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=4, Benign=1}.

BS2

High Hemizygotes in GnomAdExome4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.7172G>A	p.Arg2391His	missense_variant	45/48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 linkuse as main transcript	c.7148G>A	p.Arg2383His	missense_variant	44/47		NP_001447.2	P21333-2Q60FE5Q6NXF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.7172G>A	p.Arg2391His	missense_variant	45/48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00000887

AC:

AN:

112683

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34853

show subpopulations

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

181611

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

67481

show subpopulations

Gnomad AFR exome

AF:

0.0000806

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000147

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000838

AC:

AN:

1097591

Hom.:

Cov.:

AF XY:

0.0000992

AC XY:

AN XY:

363053

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000887

AC:

AN:

112683

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34853

show subpopulations

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000743

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	This variant is associated with the following publications: (PMID: 27193221) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 19, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2022	The FLNA c.7148G>A; p.Arg2383His variant (rs727503930) is reported in the literature in an individual affected with otopalatodigital syndrome; however, the variant was detected in the patient’s unaffected mother who was shown to have random X chromosome inactivation (Moutton 2016). This variant is also reported in ClinVar (Variation ID: 167077), and is found in the non-Finnish European population with an allele frequency of 0.015% (12/81,373 alleles, including 3 hemizygotes) in the Genome Aggregation Database. The arginine at codon 2383 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.827). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Moutton S et al. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum. J Hum Genet. 2016 Aug;61(8):693-9. PMID: 27193221. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2020

The p.R2383H variant (also known as c.7148G>A), located in coding exon 43 of the FLNA gene, results from a G to A substitution at nucleotide position 7148. The arginine at codon 2383 is replaced by histidine, an amino acid with highly similar properties. This alteration, reported as p.R2391H, has been detected in a female with clinical symptoms compatible with otopalatodigital syndrome. However, the patient also exhibited atypical findings, did not exhibit skewed X-inactivation, and inherited the variant from her unaffected mother also with random X-inactivation (Moutton S et al. J Hum Genet, 2016 Aug;61:693-9). Based on data from gnomAD, the A allele has an overall frequency of 0.007% (13/181611) total alleles studied, with 3 hemizygote(s) observed. The highest observed frequency was 0.01% (12/81373) of non-Finnish European alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;.;.

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.4

M;.;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.2

D;.;D;D;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.019

D;.;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;.;P;P;.

Vest4

0.71

MutPred

0.57

Gain of sheet (P = 0.0344);.;.;.;.;

MVP

0.99

MPC

1.6

ClinPred

0.51

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.80

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over