rs782129236

Positions:

• chrX-154359038-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PP2 PP3_Moderate BP6

The NM_001110556.2(FLNA):​c.4420G>A​(p.Asp1474Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,285 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 7.83

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]

FLNA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNA. . Gene score misZ 3.7802 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked Ehlers-Danlos syndrome, terminal osseous dysplasia-pigmentary defects syndrome, FG syndrome 2, frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, otopalatodigital syndrome type 2, periventricular nodular heterotopia, otopalatodigital syndrome type 1, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, familial thoracic aortic aneurysm and aortic dissection, congenital short bowel syndrome, frontometaphyseal dysplasia 1, cardiac valvular dysplasia, X-linked.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• BP6: Variant X-154359038-C-T is Benign according to our data. Variant chrX-154359038-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195948.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.4420G>A	p.Asp1474Asn	missense_variant	26/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.4420G>A	p.Asp1474Asn	missense_variant	26/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.4420G>A	p.Asp1474Asn	missense_variant	26/48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000165 AC: 3 AN: 181641 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67627

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000221

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097285 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363073

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 28, 2023	PP2 -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 28, 2015	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2021

The p.D1474N variant (also known as c.4420G>A), located in coding exon 25 of the FLNA gene, results from a G to A substitution at nucleotide position 4420. The aspartic acid at codon 1474 is replaced by asparagine, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (3/181641) total alleles studied, with no hemizygotes observed. The highest observed frequency was 0.02% (3/13553) of East Asian alleles. This amino acid position is highly 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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.6	M;.;M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D;.;D;D;.
REVEL	Uncertain	0.64
Sift	Benign	0.061	T;.;T;T;.
Sift4G	Uncertain	0.023	D;D;D;D;T
Polyphen		1.0	D;.;D;D;.
Vest4		0.64
MutPred		0.57		Gain of MoRF binding (P = 0.0617);.;Gain of MoRF binding (P = 0.0617);Gain of MoRF binding (P = 0.0617);.;
MVP		0.96
MPC		1.4
ClinPred		0.77	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.70
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs782129236; hg19: chrX-153587406;