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rs371092631

chrX-154367533-G-AchrX-154367533-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001110556.2(FLNA):c.732C>T(p.Pro244=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,209,898 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 83 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P244P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., 6 hem., cov: 24)
Exomes 𝑓: 0.00020 ( 0 hom. 77 hem. )

Consequence

FLNA
NM_001110556.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.29
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 -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant X-154367533-G-A is Benign according to our data. Variant chrX-154367533-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 197728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154367533-G-A is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.29 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000196 (215/1097659) while in subpopulation MID AF= 0.00314 (13/4136). AF 95% confidence interval is 0.00186. There are 0 homozygotes in gnomad4_exome. There are 77 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FLNANM_001110556.2 linkuse as main transcriptc.732C>T p.Pro244= synonymous_variant 5/48 ENST00000369850.10
FLNANM_001456.4 linkuse as main transcriptc.732C>T p.Pro244= synonymous_variant 5/47

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FLNAENST00000369850.10 linkuse as main transcriptc.732C>T p.Pro244= synonymous_variant 5/481 NM_001110556.2 P21333-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000196
AC:
22
AN:
112239
Hom.:
0
Cov.:
24
AF XY:
0.000174
AC XY:
6
AN XY:
34423
show subpopulations
Gnomad AFR
AF:
0.0000324
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000934
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:
0.000377
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000281
AC:
51
AN:
181729
Hom.:
0
AF XY:
0.000311
AC XY:
21
AN XY:
67525
show subpopulations
Gnomad AFR exome
AF:
0.000159
Gnomad AMR exome
AF:
0.000110
Gnomad ASJ exome
AF:
0.000134
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000315
Gnomad FIN exome
AF:
0.0000629
Gnomad NFE exome
AF:
0.000418
Gnomad OTH exome
AF:
0.000895
GnomAD4 exome
AF:
0.000196
AC:
215
AN:
1097659
Hom.:
0
Cov.:
32
AF XY:
0.000212
AC XY:
77
AN XY:
363269
show subpopulations
Gnomad4 AFR exome
AF:
0.000189
Gnomad4 AMR exome
AF:
0.000170
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000443
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000173
Gnomad4 OTH exome
AF:
0.000391
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000196
AC:
22
AN:
112239
Hom.:
0
Cov.:
24
AF XY:
0.000174
AC XY:
6
AN XY:
34423
show subpopulations
Gnomad4 AFR
AF:
0.0000324
Gnomad4 AMR
AF:
0.0000934
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000377
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000436
Hom.:
2
Bravo
AF:
0.000234
EpiCase
AF:
0.000491
EpiControl
AF:
0.000711

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 15, 2024- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 29, 2015- -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022FLNA: BP4, BP7 -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 27, 2020- -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 25, 2016This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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 testingInvitaeJan 27, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
Cadd
Benign
0.32
Dann
Benign
0.81
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

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

Other links and lift over

dbSNP: rs371092631; hg19: chrX-153595901; COSMIC: COSV105910589; COSMIC: COSV105910589; API