rs2070825

chrX-154353564-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001110556.2(FLNA):c.5850T>C(p.Ala1950=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,209,033 control chromosomes in the GnomAD database, including 11,142 homozygotes. There are 54,049 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3218 hom., 7419 hem., cov: 25)
  • Exomes 𝑓: 0.13 (7924 hom. 46630 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.47

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-154353564-A-G is Benign according to our data. Variant chrX-154353564-A-G is described in ClinVar as [Benign]. Clinvar id is 93766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154353564-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.5850T>C	p.Ala1950=	synonymous_variant	36/48	ENST00000369850.10
FLNA	NM_001456.4	c.5826T>C	p.Ala1942=	synonymous_variant	35/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.5850T>C	p.Ala1950=	synonymous_variant	36/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.223 AC: 24965 AN: 112013 Hom.: 3205 Cov.: 25 AF XY: 0.216 AC XY: 7380 AN XY: 34245

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.00437

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.0560

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0588

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.155 AC: 28172 AN: 181171 Hom.: 2226 AF XY: 0.146 AC XY: 9788 AN XY: 67041

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.0735

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.129 AC: 141332 AN: 1096966 Hom.: 7924 Cov.: 33 AF XY: 0.129 AC XY: 46630 AN XY: 362626

Gnomad4 AFR exome AF: 0.503

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.223 AC: 25028 AN: 112067 Hom.: 3218 Cov.: 25 AF XY: 0.216 AC XY: 7419 AN XY: 34309

Gnomad4 AFR AF: 0.492

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.0560

Gnomad4 EAS AF: 0.0925

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.205

Alfa AF: 0.138 Hom.: 2967

Bravo AF: 0.240

EpiCase AF: 0.102

EpiControl AF: 0.0903

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2013	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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Apr 17, 2012	- -
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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	8.6
Dann	Benign	0.58

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: rs2070825; hg19: chrX-153581932; COSMIC: COSV61039995; COSMIC: COSV61039995;