rs782069230

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP6_Very_StrongBS1

The NM_001110556.2(FLNA):c.6217C>T(p.Arg2073Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,209,245 control chromosomes in the GnomAD database, including 1 homozygotes. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2073H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000024 ( 1 hom. 1 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.383

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 Benign. Variant got -11 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNA

BP6

Variant X-154353010-G-A is Benign according to our data. Variant chrX-154353010-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000237 (26/1096705) while in subpopulation AMR AF= 0.000654 (23/35195). AF 95% confidence interval is 0.000446. There are 1 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.6217C>T	p.Arg2073Cys	missense_variant	38/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.6193C>T	p.Arg2065Cys	missense_variant	37/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.6217C>T	p.Arg2073Cys	missense_variant	38/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112540

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34700

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000280

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:

0.000116

AC:

AN:

180855

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67157

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000731

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000526

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1096705

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362367

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000654

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112540

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34700

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000280

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:

0.0000264

ExAC

AF:

0.0000827

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Invitae

Jan 07, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

FLNA-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.45

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.;.

FATHMM_MKL

Benign

0.63

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Uncertain

0.67

D;D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

3.3

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-7.2

D;.;D;D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.77

MutPred

0.60

Gain of sheet (P = 0.0221);.;.;.;.;

MVP

0.98

MPC

1.6

ClinPred

0.70

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.89

gMVP

0.73

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