rs72616474

Positions:

chrX-154353214-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.6023-10C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,209,747 control chromosomes in the GnomAD database, including 4 homozygotes. There are 493 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., 80 hem., cov: 25)

Exomes 𝑓: 0.0012 ( 4 hom. 413 hem. )

Consequence

FLNA
NM_001110556.2 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.001091

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.649

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant X-154353214-G-C is Benign according to our data. Variant chrX-154353214-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 211021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154353214-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00148 (167/112589) while in subpopulation EAS AF= 0.0246 (88/3570). AF 95% confidence interval is 0.0205. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 80 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.6023-10C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.5999-10C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.6023-10C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

168

AN:

112535

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

AN XY:

34681

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0249

Gnomad SAS

AF:

0.000363

Gnomad FIN

AF:

0.0111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.000657

GnomAD3 exomes

AF:

0.00368

AC:

668

AN:

181586

Hom.:

AF XY:

0.00363

AC XY:

245

AN XY:

67550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.000402

Gnomad EAS exome

AF:

0.0306

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00879

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00224

GnomAD4 exome

AF:

0.00119

AC:

1306

AN:

1097158

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

413

AN XY:

362728

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000170

Gnomad4 ASJ exome

AF:

0.000206

Gnomad4 EAS exome

AF:

0.0187

Gnomad4 SAS exome

AF:

0.000277

Gnomad4 FIN exome

AF:

0.0106

Gnomad4 NFE exome

AF:

0.000195

Gnomad4 OTH exome

AF:

0.00276

GnomAD4 genome

AF:

0.00148

AC:

167

AN:

112589

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

AN XY:

34745

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0246

Gnomad4 SAS

AF:

0.000364

Gnomad4 FIN

AF:

0.0111

Gnomad4 NFE

AF:

0.000150

Gnomad4 OTH

AF:

0.000649

Alfa

AF:

0.000436

Hom.:

Bravo

AF:

0.00125

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 23, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2024	Variant summary: FLNA c.6023-10C>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0037 in 181586 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 11771-fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNA causing Periventricular Nodular Heterotopia phenotype (3.1e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.6023-10C>G in individuals affected with Periventricular Nodular Heterotopia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 211021). Based on the evidence outlined above, the variant was classified as benign. -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0011

dbscSNV1_RF

Benign

0.21

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over