rs199853721

chrX-154366598-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001110556.2(FLNA):c.1029C>T(p.Ser343=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,210,788 control chromosomes in the GnomAD database, including 3 homozygotes. There are 571 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).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., 32 hem., cov: 25)
  • Exomes 𝑓: 0.0016 (2 hom. 539 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -1.69

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-154366598-G-A is Benign according to our data. Variant chrX-154366598-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198468.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=2, Uncertain_significance=1}. Variant chrX-154366598-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0011 (124/112909) while in subpopulation NFE AF= 0.00199 (106/53236). AF 95% confidence interval is 0.00168. There are 1 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.1029C>T	p.Ser343=	synonymous_variant	7/48	ENST00000369850.10
FLNA	NM_001456.4	c.1029C>T	p.Ser343=	synonymous_variant	7/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.1029C>T	p.Ser343=	synonymous_variant	7/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 124 AN: 112856 Hom.: 1 Cov.: 25 AF XY: 0.000914 AC XY: 32 AN XY: 34992

Gnomad AFR AF: 0.000258

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.000370

Gnomad ASJ AF: 0.000755

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.000920 AC: 167 AN: 181600 Hom.: 0 AF XY: 0.000961 AC XY: 65 AN XY: 67628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.0000738

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.00157 AC: 1727 AN: 1097879 Hom.: 2 Cov.: 32 AF XY: 0.00148 AC XY: 539 AN XY: 363263

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.000994

Gnomad4 ASJ exome AF: 0.000774

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000742

Gnomad4 NFE exome AF: 0.00192

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00110 AC: 124 AN: 112909 Hom.: 1 Cov.: 25 AF XY: 0.000913 AC XY: 32 AN XY: 35055

Gnomad4 AFR AF: 0.000257

Gnomad4 AMR AF: 0.000370

Gnomad4 ASJ AF: 0.000755

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.00194

Alfa AF: 0.000982 Hom.: 7

Bravo AF: 0.00111

EpiCase AF: 0.00104

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 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	Athena Diagnostics	Mar 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2023	- -

not provided Benign:5

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	Dec 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2014

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	2.7
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199853721; hg19: chrX-153594966; COSMIC: COSV100774203; COSMIC: COSV100774203;