rs797045580

Variant names:

• chrX-154352888-C-T
• rs797045580
• NM_001110556.2:c.6263G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001110556.2(FLNA):​c.6263G>A​(p.Ser2088Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,779 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S2088S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.78
• Publications: 0 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked

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

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

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

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, 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: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.6263G>A	p.Ser2088Asn	missense	Exon 39 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.6239G>A	p.Ser2080Asn	missense	Exon 38 of 47	NP_001447.2	P21333-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.6263G>A	p.Ser2088Asn	missense	Exon 39 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.6239G>A	p.Ser2080Asn	missense	Exon 37 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.6182G>A	p.Ser2061Asn	missense	Exon 38 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097779 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363279

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841955

Other (OTH) AF: 0.00 AC: 0 AN: 46086

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.82	P
Vest4		0.73
MutPred		0.44		Loss of phosphorylation at S2088 (P = 0.0678)
MVP		0.97
MPC		1.1
ClinPred		0.99	D
GERP RS		5.5
PromoterAI		0.021	Neutral
Varity_R		0.95
gMVP		0.68
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs797045580; hg19: chrX-153581256;