rs137853318

Positions:

• chrX-154367732-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001110556.2(FLNA):​c.629G>T​(p.Cys210Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001110556.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FLNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant X-154367732-C-A is Pathogenic according to our data. Variant chrX-154367732-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11773.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154367732-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.629G>T	p.Cys210Phe	missense_variant	4/48	ENST00000369850.10
FLNA	NM_001456.4	c.629G>T	p.Cys210Phe	missense_variant	4/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.629G>T	p.Cys210Phe	missense_variant	4/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Oto-palato-digital syndrome, type II Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.93	D;.;.;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.5	L;.;L;L;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-9.4	D;.;D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;D;.
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		0.99	D;.;P;P;.
Vest4		0.91
MutPred		0.84		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;
MVP		1.0
MPC		3.4
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853318; hg19: chrX-153596100;