rs1060500721

Variant names:

• chrX-154348991-C-T
• rs1060500721
• NM_001110556.2:c.7802G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001110556.2(FLNA):​c.7802G>A​(p.Cys2601Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000082 in 1,097,482 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2601G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.84
• 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, 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL,AD,AR gene

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.7802G>A	p.Cys2601Tyr	missense	Exon 48 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.7778G>A	p.Cys2593Tyr	missense	Exon 47 of 47	NP_001447.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.7802G>A	p.Cys2601Tyr	missense	Exon 48 of 48	ENSP00000358866.3
	FLNA	ENST00000360319.9	TSL:1	c.7778G>A	p.Cys2593Tyr	missense	Exon 46 of 46	ENSP00000353467.4
	FLNA	ENST00000369856.8	TSL:1	c.7721G>A	p.Cys2574Tyr	missense	Exon 47 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097482 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363126

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35185

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40089

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 841935

Other (OTH) AF: 0.0000217 AC: 1 AN: 46074

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.5	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.49		Loss of catalytic residue at P2600 (P = 0.0135)
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.95
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060500721; hg19: chrX-153577359;