ENST00000490936.5:n.5290C>T

Variant names:

• chrX-154348732-G-A
• rs149379012
• ENST00000490936.5:n.5290C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000490936.5(FLNA):​n.5290C>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 0.006 in 653,514 control chromosomes in the GnomAD database, including 120 homozygotes. There are 1,004 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (80 hom., 663 hem., cov: 24)
  • Exomes 𝑓: 0.0027 (40 hom. 341 hem.)
• Consequence: FLNA ENST00000490936.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.360
• Publications: 0 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-154348732-G-A is Benign according to our data. Variant chrX-154348732-G-A is described in ClinVar as [Benign]. Clinvar id is 1242239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.*117C>T		3_prime_UTR_variant	Exon 48 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.*117C>T		3_prime_UTR_variant	Exon 47 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.*117C>T		3_prime_UTR_variant	Exon 48 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 2455 AN: 110218 Hom.: 80 Cov.: 24

Gnomad AFR AF: 0.0781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00677

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000247

Gnomad OTH AF: 0.0259

GnomAD4 exome AF: 0.00268 AC: 1457 AN: 543251 Hom.: 40 Cov.: 8 AF XY: 0.00228 AC XY: 341 AN XY: 149643

African (AFR) AF: 0.0777 AC: 1096 AN: 14098

American (AMR) AF: 0.00504 AC: 92 AN: 18262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11808

East Asian (EAS) AF: 0.00 AC: 0 AN: 24757

South Asian (SAS) AF: 0.0000884 AC: 3 AN: 33951

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30935

Middle Eastern (MID) AF: 0.00507 AC: 14 AN: 2760

European-Non Finnish (NFE) AF: 0.000250 AC: 95 AN: 379689

Other (OTH) AF: 0.00582 AC: 157 AN: 26991

GnomAD4 genome AF: 0.0223 AC: 2461 AN: 110263 Hom.: 80 Cov.: 24 AF XY: 0.0204 AC XY: 663 AN XY: 32513

African (AFR) AF: 0.0782 AC: 2336 AN: 29890

American (AMR) AF: 0.00676 AC: 71 AN: 10499

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3515

South Asian (SAS) AF: 0.00 AC: 0 AN: 2651

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5950

Middle Eastern (MID) AF: 0.00926 AC: 2 AN: 216

European-Non Finnish (NFE) AF: 0.000247 AC: 13 AN: 52691

Other (OTH) AF: 0.0256 AC: 39 AN: 1525

Alfa AF: 0.0167 Hom.: 56

Bravo AF: 0.0255

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.5
DANN	Benign	0.75
PhyloP100		-0.36
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.5
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

Other links and lift over

dbSNP: rs149379012; hg19: chrX-153577100;