rs1557180226

chrX-154371164-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000369856.8(FLNA):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 25)
• Consequence: FLNA ENST00000369856.8 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.22

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 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154371164-T-C is Pathogenic according to our data. Variant chrX-154371164-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 488068.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.82A>G	p.Met28Val	missense_variant	2/48	ENST00000369850.10
FLNA	NM_001456.4	c.82A>G	p.Met28Val	missense_variant	2/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.82A>G	p.Met28Val	missense_variant	2/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Heterotopia, periventricular, X-linked dominant Pathogenic:1

Pathogenic, no assertion criteria provided

research

Clinical Genetics Group, University of Otago

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	22
Dann	Benign	0.92
DEOGEN2	Uncertain	0.72	D;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.50	T;D;T;T;D
MetaSVM	Uncertain	0.087	D
MutationAssessor	Benign	1.3	L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D;D;D;D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;D;D;.
Sift4G	Benign	0.072	T;D;T;T;D
Polyphen		0.22	B;.;P;P;.
Vest4		0.43
MutPred		0.17		Loss of loop (P = 0.0804);.;Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;
MVP		0.98
MPC		2.2
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.76
gMVP		0.87

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: rs1557180226; hg19: chrX-153599532;