rs2073470

Positions:

chrX-154367698-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001110556.2(FLNA):c.663C>T(p.Pro221=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,209,832 control chromosomes in the GnomAD database, including 154 homozygotes. There are 1,500 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P221P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0052 ( 12 hom., 186 hem., cov: 25)

Exomes 𝑓: 0.0043 ( 142 hom. 1314 hem. )

Consequence

FLNA
NM_001110556.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -4.24

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant X-154367698-G-A is Benign according to our data. Variant chrX-154367698-G-A is described in ClinVar as [Benign]. Clinvar id is 93771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154367698-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-4.24 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.663C>T	p.Pro221=	synonymous_variant	4/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.663C>T	p.Pro221=	synonymous_variant	4/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.663C>T	p.Pro221=	synonymous_variant	4/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00509

AC:

572

AN:

112354

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

184

AN XY:

34526

show subpopulations

Gnomad AFR

AF:

0.000452

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0387

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0329

Gnomad SAS

AF:

0.00182

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.00728

GnomAD3 exomes

AF:

0.0157

AC:

2842

AN:

181390

Hom.:

104

AF XY:

0.0110

AC XY:

745

AN XY:

67524

show subpopulations

Gnomad AFR exome

AF:

0.000403

Gnomad AMR exome

AF:

0.0816

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0379

Gnomad SAS exome

AF:

0.000944

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.0128

GnomAD4 exome

AF:

0.00426

AC:

4677

AN:

1097423

Hom.:

142

Cov.:

AF XY:

0.00362

AC XY:

1314

AN XY:

363255

show subpopulations

Gnomad4 AFR exome

AF:

0.000682

Gnomad4 AMR exome

AF:

0.0762

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0535

Gnomad4 SAS exome

AF:

0.000979

Gnomad4 FIN exome

AF:

0.0000251

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.00436

GnomAD4 genome

AF:

0.00517

AC:

581

AN:

112409

Hom.:

Cov.:

AF XY:

0.00538

AC XY:

186

AN XY:

34591

show subpopulations

Gnomad4 AFR

AF:

0.000451

Gnomad4 AMR

AF:

0.0394

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0330

Gnomad4 SAS

AF:

0.00219

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000188

Gnomad4 OTH

AF:

0.00718

Alfa

AF:

0.00360

Hom.:

Bravo

AF:

0.00941

EpiCase

AF:

0.000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Mar 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2015

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.17

DANN

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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