rs111516546

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP6

The NM_001110556.2(FLNA):c.1900C>T(p.Arg634Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,208,765 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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. R634G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 1 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.24

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 Uncertain_significance. Variant got 0 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.

BP6

Variant X-154364648-G-A is Benign according to our data. Variant chrX-154364648-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2631579.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chrX-154364648-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.1900C>T	p.Arg634Cys	missense_variant	13/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.1900C>T	p.Arg634Cys	missense_variant	13/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.1900C>T	p.Arg634Cys	missense_variant	13/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111210

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33410

show subpopulations

Gnomad AFR

AF:

0.0000655

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

GnomAD3 exomes

AF:

0.0000220

AC:

AN:

181467

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67499

show subpopulations

Gnomad AFR exome

AF:

0.000242

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097555

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363215

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

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:

0.00000356

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111210

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33410

show subpopulations

Gnomad4 AFR

AF:

0.0000655

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

FLNA-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2023

The FLNA c.1900C>T variant is predicted to result in the amino acid substitution p.Arg634Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-153593016-G-A). Although we suspect that this variant may be benign, 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.;.;.;.

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.94

D;D;.;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.6

M;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.0

D;.;D;D;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.0010

D;.;D;D;.

Sift4G

Uncertain

0.055

T;T;T;T;T

Polyphen

1.0

D;.;P;P;.

Vest4

0.74

MVP

0.95

MPC

1.6

ClinPred

0.44

GERP RS

5.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.82

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -15

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