rs782557713

chrX-154349751-G-AchrX-154349751-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001110556.2(FLNA):c.7450C>T(p.Arg2484Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,210,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 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. R2484H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 4 hem., cov: 26)
  • Exomes 𝑓: 0.000078 (0 hom. 26 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.981

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 -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.2148794).
• BP6: Variant X-154349751-G-A is Benign according to our data. Variant chrX-154349751-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213510.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=1}. Variant chrX-154349751-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000784 (86/1097378) while in subpopulation MID AF= 0.0017 (7/4121). AF 95% confidence interval is 0.000797. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.7450C>T	p.Arg2484Cys	missense_variant	46/48	ENST00000369850.10
FLNA	NM_001456.4	c.7426C>T	p.Arg2476Cys	missense_variant	45/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.7450C>T	p.Arg2484Cys	missense_variant	46/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000974 AC: 11 AN: 112932 Hom.: 0 Cov.: 26 AF XY: 0.000114 AC XY: 4 AN XY: 35082

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000371

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: 0.000131

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000166 AC: 30 AN: 180873 Hom.: 0 AF XY: 0.000134 AC XY: 9 AN XY: 67281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000223

Gnomad OTH exome AF: 0.000676

GnomAD4 exome AF: 0.0000784 AC: 86 AN: 1097378 Hom.: 0 Cov.: 32 AF XY: 0.0000716 AC XY: 26 AN XY: 363014

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000312

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.0000250

Gnomad4 NFE exome AF: 0.0000618

Gnomad4 OTH exome AF: 0.000260

GnomAD4 genome AF: 0.0000885 AC: 10 AN: 112985 Hom.: 0 Cov.: 26 AF XY: 0.000114 AC XY: 4 AN XY: 35145

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000371

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000306

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	This variant is associated with the following publications: (PMID: 30986657) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

FLNA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2020

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	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.;.
FATHMM_MKL	Benign	0.40	N
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.6	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.2	D;.;D;D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.029	D;.;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.98	D;.;D;D;.
Vest4		0.30
MutPred		0.62		Gain of catalytic residue at T2486 (P = 0.0598);.;.;.;.;
MVP		0.91
MPC		1.1
ClinPred		0.10	T
GERP RS		3.7
Varity_R		0.28
gMVP		0.63

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

Other links and lift over

dbSNP: rs782557713; hg19: chrX-153578119; COSMIC: COSV61046986; COSMIC: COSV61046986;