ENST00000490936.5:n.5261C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000490936.5(FLNA):​n.5261C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00897 in 855,097 control chromosomes in the GnomAD database, including 35 homozygotes. There are 2,047 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 0.0067 ( 0 hom., 196 hem., cov: 23)
Exomes 𝑓: 0.0093 ( 35 hom. 1851 hem. )

Consequence

FLNA
ENST00000490936.5 non_coding_transcript_exon

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.28

Publications

1 publications found
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 Gene-Disease associations (from GenCC):
  • periventricular nodular heterotopia
    Inheritance: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • frontometaphyseal dysplasia 1
    Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
  • genetic developmental and epileptic encephalopathy
    Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
  • heterotopia, periventricular, X-linked dominant
    Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
  • intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked
    Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • Melnick-Needles syndrome
    Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
  • otopalatodigital syndrome type 2
    Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • terminal osseous dysplasia-pigmentary defects syndrome
    Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
  • cardiac valvular dysplasia, X-linked
    Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • frontometaphyseal dysplasia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital short bowel syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • otopalatodigital syndrome type 1
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • X-linked Ehlers-Danlos syndrome
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • familial thoracic aortic aneurysm and aortic dissection
    Inheritance: XL Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant X-154348761-G-A is Benign according to our data. Variant chrX-154348761-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1199805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00666 (685/102882) while in subpopulation NFE AF = 0.0105 (533/50741). AF 95% confidence interval is 0.00977. There are 0 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
BS2
High Hemizygotes in GnomAd4 at 196 XL,AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNANM_001110556.2 linkc.*88C>T 3_prime_UTR_variant Exon 48 of 48 ENST00000369850.10 NP_001104026.1 P21333-1Q60FE5Q6NXF2
FLNANM_001456.4 linkc.*88C>T 3_prime_UTR_variant Exon 47 of 47 NP_001447.2 P21333-2Q60FE5Q6NXF2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNAENST00000369850.10 linkc.*88C>T 3_prime_UTR_variant Exon 48 of 48 1 NM_001110556.2 ENSP00000358866.3 P21333-1

Frequencies

GnomAD3 genomes
AF:
0.00666
AC:
685
AN:
102877
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.00146
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000921
Gnomad ASJ
AF:
0.0249
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00167
Gnomad FIN
AF:
0.00593
Gnomad MID
AF:
0.00441
Gnomad NFE
AF:
0.0105
Gnomad OTH
AF:
0.00214
GnomAD4 exome
AF:
0.00928
AC:
6981
AN:
752215
Hom.:
35
Cov.:
13
AF XY:
0.00894
AC XY:
1851
AN XY:
207103
show subpopulations
African (AFR)
AF:
0.00102
AC:
17
AN:
16717
American (AMR)
AF:
0.00128
AC:
26
AN:
20254
Ashkenazi Jewish (ASJ)
AF:
0.0217
AC:
295
AN:
13603
East Asian (EAS)
AF:
0.0000388
AC:
1
AN:
25758
South Asian (SAS)
AF:
0.00199
AC:
75
AN:
37605
European-Finnish (FIN)
AF:
0.00689
AC:
206
AN:
29884
Middle Eastern (MID)
AF:
0.000680
AC:
2
AN:
2940
European-Non Finnish (NFE)
AF:
0.0107
AC:
6133
AN:
571627
Other (OTH)
AF:
0.00668
AC:
226
AN:
33827
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
240
480
719
959
1199
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
218
436
654
872
1090
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00666
AC:
685
AN:
102882
Hom.:
0
Cov.:
23
AF XY:
0.00683
AC XY:
196
AN XY:
28686
show subpopulations
African (AFR)
AF:
0.00146
AC:
38
AN:
26095
American (AMR)
AF:
0.000920
AC:
9
AN:
9783
Ashkenazi Jewish (ASJ)
AF:
0.0249
AC:
64
AN:
2575
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3437
South Asian (SAS)
AF:
0.00167
AC:
4
AN:
2391
European-Finnish (FIN)
AF:
0.00593
AC:
33
AN:
5566
Middle Eastern (MID)
AF:
0.00485
AC:
1
AN:
206
European-Non Finnish (NFE)
AF:
0.0105
AC:
533
AN:
50741
Other (OTH)
AF:
0.00214
AC:
3
AN:
1403
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
22
44
67
89
111
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00594
Hom.:
27
Bravo
AF:
0.00526

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jun 26, 2018
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.37
DANN
Benign
0.61
PhyloP100
-3.3
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.3
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs55760624; hg19: chrX-153577129; API