rs797045044

Variant names:

• chrX-154358228-C-T
• rs797045044
• NM_001110556.2:c.4726G>A
• FLNA p.Gly1576Arg

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001110556.2(FLNA):​c.4726G>A​(p.Gly1576Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,462 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1576W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.83
• Publications: 8 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: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• otopalatodigital syndrome type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154358228-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3342232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-154358228-C-T is Pathogenic according to our data. Variant chrX-154358228-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 209154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4726G>A	p.Gly1576Arg	missense	Exon 28 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.4726G>A	p.Gly1576Arg	missense	Exon 28 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.4726G>A	p.Gly1576Arg	missense	Exon 28 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.4726G>A	p.Gly1576Arg	missense	Exon 27 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.4645G>A	p.Gly1549Arg	missense	Exon 27 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112500 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1096962 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362942

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 54107

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39585

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

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841949

Other (OTH) AF: 0.00 AC: 0 AN: 46066

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112500 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34660

African (AFR) AF: 0.00 AC: 0 AN: 30939

American (AMR) AF: 0.00 AC: 0 AN: 10763

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2741

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6237

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53172

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Cardiac valvular dysplasia, X-linked (1)
1	-	-	Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.89
gMVP		0.87
Mutation Taster		=1/99	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs797045044;

hg19: chrX-153586596;