rs200130356

chrX-154359007-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001110556.2(FLNA):c.4451A>G(p.Gln1484Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,209,895 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 558 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1484H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., 26 hem., cov: 24)
  • Exomes 𝑓: 0.0014 (0 hom. 532 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:16
• Conservation: PhyloP100: 4.99

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.0398449).
• BP6: Variant X-154359007-T-C is Benign according to our data. Variant chrX-154359007-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190194.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=6, Uncertain_significance=1}. Variant chrX-154359007-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000844 (95/112552) while in subpopulation NFE AF= 0.00156 (83/53128). AF 95% confidence interval is 0.00129. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.4451A>G	p.Gln1484Arg	missense_variant	26/48	ENST00000369850.10
FLNA	NM_001456.4	c.4451A>G	p.Gln1484Arg	missense_variant	26/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.4451A>G	p.Gln1484Arg	missense_variant	26/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.000844 AC: 95 AN: 112497 Hom.: 0 Cov.: 24 AF XY: 0.000750 AC XY: 26 AN XY: 34669

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000933

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000726

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00102 AC: 186 AN: 181561 Hom.: 0 AF XY: 0.00115 AC XY: 78 AN XY: 67537

Gnomad AFR exome AF: 0.000404

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.000268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.000315

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.00144 AC: 1578 AN: 1097343 Hom.: 0 Cov.: 33 AF XY: 0.00146 AC XY: 532 AN XY: 363145

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.000754

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000844 AC: 95 AN: 112552 Hom.: 0 Cov.: 24 AF XY: 0.000749 AC XY: 26 AN XY: 34734

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000932

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000728

Gnomad4 FIN AF: 0.000161

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00130 Hom.: 59

Bravo AF: 0.000718

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00277 AC: 8

ESP6500AA AF: 0.000279 AC: 1

ESP6500EA AF: 0.00152 AC: 10

ExAC AF: 0.00127 AC: 154

EpiCase AF: 0.00153

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 12, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	FLNA: PP2, BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2020	This variant is associated with the following publications: (PMID: 21836662, 28074886) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2016	- -

Heterotopia, periventricular, X-linked dominant Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Claritas Genomics	Mar 04, 2013	- -

Aortic dilatation Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

May 31, 2017

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2017

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

Jan 29, 2024

- -

Thrombocytopenia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.040	T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.84	L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	N;.;N;N;.
REVEL	Uncertain	0.54
Sift	Benign	0.12	T;.;T;T;.
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.060	B;.;P;P;.
Vest4		0.48
MVP		0.96
MPC		0.55
ClinPred		0.026	T
GERP RS		5.7
Varity_R		0.46
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs200130356; hg19: chrX-153587375;