rs376726422

Positions:

chrX-154360184-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_001110556.2(FLNA):c.3611C>T(p.Pro1204Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,209,070 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000014 ( 0 hom. 5 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.31711066).

BP6

Variant X-154360184-G-A is Benign according to our data. Variant chrX-154360184-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533565.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.3611C>T	p.Pro1204Leu	missense_variant	22/48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 linkuse as main transcript	c.3611C>T	p.Pro1204Leu	missense_variant	22/47		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.3611C>T	p.Pro1204Leu	missense_variant	22/48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000176

AC:

AN:

113505

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

35645

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:

0.000157

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000446

AC:

AN:

179518

Hom.:

AF XY:

0.0000748

AC XY:

AN XY:

66824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000526

Gnomad FIN exome

AF:

0.0000630

Gnomad NFE exome

AF:

0.0000501

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1095565

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361819

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000952

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000176

AC:

AN:

113505

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

35645

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:

0.000157

Gnomad4 NFE

AF:

0.0000187

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000152

AC:

ExAC

AF:

0.0000496

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

The p.P1204L variant (also known as c.3611C>T), located in coding exon 21 of the FLNA gene, results from a C to T substitution at nucleotide position 3611. The proline at codon 1204 is replaced by leucine, an amino acid with similar properties. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (9/201479) total alleles studied, with 6 hemizygote(s) observed. The highest observed frequency was <0.01% (1/5226) of Other alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of FLNA-related otopalatodigital spectrum disorder; however, its contribution to the development of FLNA-related periventricular nodular heterotopia is uncertain. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

D;.;.;.;.

FATHMM_MKL

Benign

0.35

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.1

L;.;L;L;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.2

N;.;N;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.058

T;.;T;T;.

Sift4G

Uncertain

0.0070

D;D;D;D;D

Polyphen

0.48

P;.;B;B;.

Vest4

0.30

MVP

0.86

MPC

0.62

ClinPred

0.073

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.22

gMVP

0.29

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

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