rs1382076574

Positions:

• chrX-154354654-G-A
• chrX-154354654-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_001110556.2(FLNA):​c.5275C>T​(p.Pro1759Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1759A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 26)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNA. . Gene score misZ 3.7802 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked Ehlers-Danlos syndrome, terminal osseous dysplasia-pigmentary defects syndrome, FG syndrome 2, frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, otopalatodigital syndrome type 2, periventricular nodular heterotopia, otopalatodigital syndrome type 1, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, familial thoracic aortic aneurysm and aortic dissection, congenital short bowel syndrome, frontometaphyseal dysplasia 1, cardiac valvular dysplasia, X-linked.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12925917).
• BP6: Variant X-154354654-G-A is Benign according to our data. Variant chrX-154354654-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 547386.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.5275C>T	p.Pro1759Ser	missense_variant	32/48	ENST00000369850.10
FLNA	NM_001456.4	c.5251C>T	p.Pro1751Ser	missense_variant	31/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.5275C>T	p.Pro1759Ser	missense_variant	32/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 26

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T;.;.;.;.
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.79	T;T;.;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N;.;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.010	N;.;N;N;.
REVEL	Benign	0.16
Sift	Benign	0.23	T;.;T;T;.
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.0020	B;.;B;B;.
Vest4		0.20
MutPred		0.26		Gain of sheet (P = 0.0266);.;.;.;.;
MVP		0.76
MPC		0.52
ClinPred		0.058	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.65

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: rs1382076574; hg19: chrX-153583022; COSMIC: COSV100774708; COSMIC: COSV100774708;