ENST00000490936.5:n.5257A>C

Variant names:

• chrX-154348765-T-G
• rs782243311
• ENST00000490936.5:n.5257A>C

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.5257A>C 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 0.129 in 982,339 control chromosomes in the GnomAD database, including 6,645 homozygotes. There are 36,799 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1311 hom., 5235 hem., cov: 24)
  • Exomes 𝑓: 0.13 (5334 hom. 31564 hem.)
• Consequence: FLNA ENST00000490936.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.718
• Publications: 1 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=-0.79).
• BP6: Variant X-154348765-T-G is Benign according to our data. Variant chrX-154348765-T-G is described in ClinVar as [Benign]. Clinvar id is 1258029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.*84A>C		3_prime_UTR_variant	Exon 48 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.*84A>C		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.*84A>C		3_prime_UTR_variant	Exon 48 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes AF: 0.160 AC: 17778 AN: 110890 Hom.: 1306 Cov.: 24

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.00295

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0540

Gnomad EAS AF: 0.0573

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0515

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.142

GnomAD4 exome AF: 0.126 AC: 109371 AN: 871402 Hom.: 5334 Cov.: 14 AF XY: 0.131 AC XY: 31564 AN XY: 240428

African (AFR) AF: 0.288 AC: 6104 AN: 21208

American (AMR) AF: 0.205 AC: 4974 AN: 24260

Ashkenazi Jewish (ASJ) AF: 0.0596 AC: 853 AN: 14316

East Asian (EAS) AF: 0.0706 AC: 1903 AN: 26960

South Asian (SAS) AF: 0.179 AC: 7413 AN: 41338

European-Finnish (FIN) AF: 0.154 AC: 5093 AN: 33098

Middle Eastern (MID) AF: 0.0693 AC: 202 AN: 2915

European-Non Finnish (NFE) AF: 0.116 AC: 77847 AN: 669455

Other (OTH) AF: 0.132 AC: 4982 AN: 37852

GnomAD4 genome AF: 0.161 AC: 17819 AN: 110937 Hom.: 1311 Cov.: 24 AF XY: 0.157 AC XY: 5235 AN XY: 33299

African (AFR) AF: 0.279 AC: 8494 AN: 30414

American (AMR) AF: 0.165 AC: 1757 AN: 10655

Ashkenazi Jewish (ASJ) AF: 0.0540 AC: 142 AN: 2631

East Asian (EAS) AF: 0.0563 AC: 196 AN: 3481

South Asian (SAS) AF: 0.169 AC: 454 AN: 2687

European-Finnish (FIN) AF: 0.140 AC: 841 AN: 5995

Middle Eastern (MID) AF: 0.0519 AC: 11 AN: 212

European-Non Finnish (NFE) AF: 0.108 AC: 5689 AN: 52669

Other (OTH) AF: 0.154 AC: 233 AN: 1514

Alfa AF: 0.0396 Hom.: 146

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: 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	-0.79
CADD	Benign	2.7
DANN	Benign	0.48
PhyloP100		-0.72
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: rs782243311; hg19: chrX-153577133;