rs369768801

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_001110556.2(FLNA):c.4075C>T(p.Arg1359Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,209,398 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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. R1359H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 2 hem., cov: 25)

Exomes 𝑓: 0.000011 ( 0 hom. 6 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.11

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 -2 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNA

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

BS2

High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.4075C>T	p.Arg1359Cys	missense_variant	24/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.4075C>T	p.Arg1359Cys	missense_variant	24/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.4075C>T	p.Arg1359Cys	missense_variant	24/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000714

AC:

AN:

112007

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34189

show subpopulations

Gnomad AFR

AF:

0.000195

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000388

AC:

AN:

180634

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67054

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000148

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097391

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363077

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000714

AC:

AN:

112007

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34189

show subpopulations

Gnomad4 AFR

AF:

0.000195

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:

0.0000377

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000573

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 405455; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

The p.R1359C variant (also known as c.4075C>T), located in coding exon 23 of the FLNA gene, results from a C to T substitution at nucleotide position 4075. The arginine at codon 1359 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (9/202257) total alleles studied, with 3 hemizygote(s) observed. The highest observed frequency was 0.03% (6/18200) of African 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

Invitae

Nov 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.45

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.;.

FATHMM_MKL

Benign

0.45

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.79

D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.9

M;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.3

D;.;D;D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

D;.;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.66

MVP

0.99

MPC

1.5

ClinPred

0.70

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.81

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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