rs398123622

chrX-154367741-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001110556.2(FLNA):c.623-3C>G variant causes a splice region, splice polypyrimidine tract, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.84

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.623-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000369850.10
FLNA	NM_001456.4	c.623-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.623-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Heterotopia, periventricular, X-linked dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1998

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	21
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: -1
DS_AL_spliceai		0.81		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123622; hg19: chrX-153596109;