rs113510895

chrX-154352208-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):c.6742C>T(p.Leu2248=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00929 in 1,209,725 control chromosomes in the GnomAD database, including 46 homozygotes. There are 3,547 hemizygotes in GnomAD. In-silico tool predicts 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. L2248L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (2 hom., 241 hem., cov: 25)
  • Exomes 𝑓: 0.0095 (44 hom. 3306 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant X-154352208-G-A is Benign according to our data. Variant chrX-154352208-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154352208-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00683 (773/113249) while in subpopulation NFE AF= 0.0109 (583/53333). AF 95% confidence interval is 0.0102. There are 2 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.6742C>T	p.Leu2248=	synonymous_variant	41/48	ENST00000369850.10
FLNA	NM_001456.4	c.6718C>T	p.Leu2240=	synonymous_variant	40/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.6742C>T	p.Leu2248=	synonymous_variant	41/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 773 AN: 113195 Hom.: 2 Cov.: 25 AF XY: 0.00682 AC XY: 241 AN XY: 35325

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.0146

Gnomad AMR AF: 0.00500

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.000277

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00712

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00587

GnomAD3 exomes AF: 0.00688 AC: 1222 AN: 177723 Hom.: 6 AF XY: 0.00666 AC XY: 433 AN XY: 65019

Gnomad AFR exome AF: 0.00158

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00853

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00752

GnomAD4 exome AF: 0.00954 AC: 10460 AN: 1096476 Hom.: 44 Cov.: 33 AF XY: 0.00912 AC XY: 3306 AN XY: 362490

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000167

Gnomad4 FIN exome AF: 0.00871

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00850

GnomAD4 genome AF: 0.00683 AC: 773 AN: 113249 Hom.: 2 Cov.: 25 AF XY: 0.00681 AC XY: 241 AN XY: 35389

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.00499

Gnomad4 ASJ AF: 0.0106

Gnomad4 EAS AF: 0.000278

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00712

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00580

Alfa AF: 0.00877 Hom.: 79

Bravo AF: 0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 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	Genetic Services Laboratory, University of Chicago	Feb 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Sep 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2015

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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	12
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs113510895; hg19: chrX-153580576; COSMIC: COSV100775376; COSMIC: COSV100775376;