NM_001110556.2:c.4594C>G

Variant names:

• chrX-154358449-G-C
• rs782563345
• NM_001110556.2:c.4594C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001110556.2(FLNA):​c.4594C>G​(p.Arg1532Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,693 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1532Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.66
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• periventricular nodular heterotopia

  Inheritance: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• frontometaphyseal dysplasia 1

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• heterotopia, periventricular, X-linked dominant

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Melnick-Needles syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• otopalatodigital syndrome type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• terminal osseous dysplasia-pigmentary defects syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• cardiac valvular dysplasia, X-linked

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• frontometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital short bowel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• otopalatodigital syndrome type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Ehlers-Danlos syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110556.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.4594C>G	p.Arg1532Gly	missense	Exon 27 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.4594C>G	p.Arg1532Gly	missense	Exon 27 of 47	NP_001447.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.4594C>G	p.Arg1532Gly	missense	Exon 27 of 48	ENSP00000358866.3
	FLNA	ENST00000360319.9	TSL:1	c.4594C>G	p.Arg1532Gly	missense	Exon 26 of 46	ENSP00000353467.4
	FLNA	ENST00000369856.8	TSL:1	c.4513C>G	p.Arg1505Gly	missense	Exon 26 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000552 AC: 1 AN: 181179 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097693 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363245

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40123

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842010

Other (OTH) AF: 0.00 AC: 0 AN: 46082

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.51	N
PhyloP100		9.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.47
Sift	Benign	0.38	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.66
MutPred		0.51		Loss of solvent accessibility (P = 0.0159)
MVP		0.91
MPC		0.68
ClinPred		0.56	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.51
gMVP		0.73
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782563345; hg19: chrX-153586817;