rs57108893

chrX-154354639-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001110556.2(FLNA):c.5290G>A(p.Ala1764Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,203,908 control chromosomes in the GnomAD database, including 388 homozygotes. There are 2,405 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1764A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (177 hom., 1158 hem., cov: 26)
  • Exomes 𝑓: 0.0042 (211 hom. 1247 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.772

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.0013102889).
• BP6: Variant X-154354639-C-T is Benign according to our data. Variant chrX-154354639-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154354639-C-T is described in Lovd as [Benign]. Variant chrX-154354639-C-T is described in Lovd as [Pathogenic]. Variant chrX-154354639-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.5290G>A	p.Ala1764Thr	missense_variant	32/48	ENST00000369850.10
FLNA	NM_001456.4	c.5266G>A	p.Ala1756Thr	missense_variant	31/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.5290G>A	p.Ala1764Thr	missense_variant	32/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 4245 AN: 113015 Hom.: 176 Cov.: 26 AF XY: 0.0329 AC XY: 1158 AN XY: 35187

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000526

Gnomad OTH AF: 0.0308

GnomAD3 exomes AF: 0.0107 AC: 1713 AN: 160670 Hom.: 89 AF XY: 0.00638 AC XY: 336 AN XY: 52696

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.00797

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000244

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00421 AC: 4596 AN: 1090844 Hom.: 211 Cov.: 32 AF XY: 0.00348 AC XY: 1247 AN XY: 358140

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.00928

Gnomad4 ASJ exome AF: 0.0000519

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000338

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.00979

GnomAD4 genome AF: 0.0376 AC: 4254 AN: 113064 Hom.: 177 Cov.: 26 AF XY: 0.0329 AC XY: 1158 AN XY: 35246

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000715

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000526

Gnomad4 OTH AF: 0.0304

Alfa AF: 0.00416 Hom.: 150

Bravo AF: 0.0443

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.130 AC: 434

ESP6500EA AF: 0.000779 AC: 5

ExAC AF: 0.0110 AC: 1317

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely 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	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jul 10, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 17, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	8.7
Dann	Benign	0.65
DEOGEN2	Benign	0.30	T;.;.;.;.
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.80	T;T;.;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.090	N;.;N;N;.
REVEL	Benign	0.096
Sift	Benign	0.32	T;.;T;T;.
Sift4G	Benign	0.55	T;T;T;T;T
Polyphen		0.010	B;.;B;B;.
Vest4		0.094
MPC		0.51
ClinPred		0.0017	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.049
gMVP		0.24

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: rs57108893; hg19: chrX-153583007;