chrX-154366857-G-A

Variant summary

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

The NM_001110556.2(FLNA):​c.869-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,192,833 control chromosomes in the GnomAD database, including 26 homozygotes. There are 640 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 10 hom., 303 hem., cov: 25)
Exomes 𝑓: 0.0012 ( 16 hom. 337 hem. )

Consequence

FLNA
NM_001110556.2 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00003080
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.01
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant X-154366857-G-A is Benign according to our data. Variant chrX-154366857-G-A is described in ClinVar as [Benign]. Clinvar id is 93776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154366857-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0098 (1103/112599) while in subpopulation AFR AF= 0.0344 (1067/31007). AF 95% confidence interval is 0.0327. There are 10 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FLNANM_001110556.2 linkuse as main transcriptc.869-7C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000369850.10 NP_001104026.1
FLNANM_001456.4 linkuse as main transcriptc.869-7C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant NP_001447.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FLNAENST00000369850.10 linkuse as main transcriptc.869-7C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_001110556.2 ENSP00000358866 P21333-1

Frequencies

GnomAD3 genomes
AF:
0.00980
AC:
1103
AN:
112545
Hom.:
10
Cov.:
25
AF XY:
0.00874
AC XY:
303
AN XY:
34683
show subpopulations
Gnomad AFR
AF:
0.0345
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00168
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000150
Gnomad OTH
AF:
0.00658
GnomAD3 exomes
AF:
0.00289
AC:
517
AN:
178830
Hom.:
6
AF XY:
0.00207
AC XY:
137
AN XY:
66300
show subpopulations
Gnomad AFR exome
AF:
0.0391
Gnomad AMR exome
AF:
0.00103
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000526
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000114
Gnomad OTH exome
AF:
0.000455
GnomAD4 exome
AF:
0.00118
AC:
1271
AN:
1080234
Hom.:
16
Cov.:
30
AF XY:
0.000972
AC XY:
337
AN XY:
346882
show subpopulations
Gnomad4 AFR exome
AF:
0.0391
Gnomad4 AMR exome
AF:
0.00119
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000744
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000121
Gnomad4 OTH exome
AF:
0.00218
GnomAD4 genome
AF:
0.00980
AC:
1103
AN:
112599
Hom.:
10
Cov.:
25
AF XY:
0.00872
AC XY:
303
AN XY:
34747
show subpopulations
Gnomad4 AFR
AF:
0.0344
Gnomad4 AMR
AF:
0.00168
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000150
Gnomad4 OTH
AF:
0.00650
Alfa
AF:
0.00547
Hom.:
26
Bravo
AF:
0.0115
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 21, 2023- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 08, 2013- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 08, 2014This 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, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 28, 2013- -
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 16, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.11
DANN
Benign
0.84
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000031
dbscSNV1_RF
Benign
0.0
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

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

Other links and lift over

dbSNP: rs143311779; hg19: chrX-153595225; API