rs782563602

chrX-154364584-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001110556.2(FLNA):c.1964G>A(p.Arg655His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000048 in 1,208,958 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. R655C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000049 (0 hom. 17 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.751

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.24285498).
• BP6: Variant X-154364584-C-T is Benign according to our data. Variant chrX-154364584-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422764.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2, Benign=1}.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.1964G>A	p.Arg655His	missense_variant	13/48	ENST00000369850.10
FLNA	NM_001456.4	c.1964G>A	p.Arg655His	missense_variant	13/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.1964G>A	p.Arg655His	missense_variant	13/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111580 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33754

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000378

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000387 AC: 7 AN: 180931 Hom.: 0 AF XY: 0.0000298 AC XY: 2 AN XY: 67199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000492 AC: 54 AN: 1097378 Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 17 AN XY: 363212

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000511

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111580 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33754

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000378

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 07, 2020	This FLNA variant (rs782563602) is rare (<0.1%) in a large population dataset (gnomAD: 8/202666 total alleles; 0.004%; no homozygotes) and has not been reported in the literature, to our knowledge. This variant has been reported in ClinVar. Of three bioinformatics tools queried, two predicts that the substitution would be damaging, while one predicts that it would be tolerated. The arginine residue at this position is evolutionarily conserved across most mammals assessed. We consider the clinical significance of c.1964G>A to be uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	FLNA: PP2, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	See Variant Classification Assertion Criteria. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 14, 2020

DNA sequence analysis of the FLNA gene demonstrated a sequence change, c.1964G>A, in exon 13 that results in an amino acid change, p.Arg655His. This sequence change does not appear to have been previously described in patients with FLNA-related disorders and has been described in the gnomAD database with a frequency of 0.025% in Latino populations (dbSNP rs782563602). The p.Arg655His change affects a moderately conserved amino acid residue located in a domain of the FLNA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg655His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg655His change remains unknown at this time. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2016

The p.R655H variant (also known as c.1964G>A), located in coding exon 12 of the FLNA gene, results from a G to A substitution at nucleotide position 1964. The arginine at codon 655 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Dec 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.;.;.
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Benign	0.20	N;.;N;N;.
MutationTaster	Benign	0.69	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N;.;N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.046	D;.;D;D;.
Sift4G	Uncertain	0.050	T;T;T;T;D
Polyphen		0.93	P;.;P;P;.
Vest4		0.25
MutPred		0.46		Loss of phosphorylation at S657 (P = 0.1031);.;Loss of phosphorylation at S657 (P = 0.1031);Loss of phosphorylation at S657 (P = 0.1031);.;
MVP		0.87
MPC		1.3
ClinPred		0.14	T
GERP RS		2.2
Varity_R		0.14
gMVP		0.29

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: rs782563602; hg19: chrX-153592952; COSMIC: COSV100775348; COSMIC: COSV100775348;