X-154348764-C-CCA

Variant names:

• chrX-154348764-C-CCA
• rs201431046
• ENST00000490936.5:n.5257_5258insTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001110556.2(FLNA):​c.*84_*85insTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 984,398 control chromosomes in the GnomAD database, including 6,530 homozygotes. There are 36,733 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (1311 hom., 5193 hem., cov: 24)
  • Exomes 𝑓: 0.12 (5219 hom. 31540 hem.)
• Consequence: FLNA NM_001110556.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant X-154348764-C-CCA is Benign according to our data. Variant chrX-154348764-C-CCA is described in ClinVar as [Benign]. Clinvar id is 1246232.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.*84_*85insTG		3_prime_UTR_variant	Exon 48 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.*84_*85insTG		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.*84_*85insTG		3_prime_UTR_variant	Exon 48 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 17736 AN: 111316 Hom.: 1306 Cov.: 24

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.00292

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0537

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0513

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.124 AC: 108058 AN: 873036 Hom.: 5219 Cov.: 14 AF XY: 0.130 AC XY: 31540 AN XY: 242538

African (AFR) AF: 0.286 AC: 6023 AN: 21080

American (AMR) AF: 0.204 AC: 4905 AN: 24084

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 847 AN: 14323

East Asian (EAS) AF: 0.0706 AC: 1894 AN: 26840

South Asian (SAS) AF: 0.178 AC: 7373 AN: 41418

European-Finnish (FIN) AF: 0.154 AC: 5055 AN: 32928

Middle Eastern (MID) AF: 0.0637 AC: 200 AN: 3138

European-Non Finnish (NFE) AF: 0.114 AC: 76833 AN: 671309

Other (OTH) AF: 0.130 AC: 4928 AN: 37916

GnomAD4 genome AF: 0.160 AC: 17777 AN: 111362 Hom.: 1311 Cov.: 24 AF XY: 0.154 AC XY: 5193 AN XY: 33654

African (AFR) AF: 0.277 AC: 8473 AN: 30571

American (AMR) AF: 0.164 AC: 1753 AN: 10667

Ashkenazi Jewish (ASJ) AF: 0.0537 AC: 142 AN: 2643

East Asian (EAS) AF: 0.0559 AC: 196 AN: 3504

South Asian (SAS) AF: 0.164 AC: 444 AN: 2705

European-Finnish (FIN) AF: 0.139 AC: 840 AN: 6055

Middle Eastern (MID) AF: 0.0516 AC: 11 AN: 213

European-Non Finnish (NFE) AF: 0.108 AC: 5685 AN: 52798

Other (OTH) AF: 0.152 AC: 231 AN: 1521

Alfa AF: 0.0329 Hom.: 146

Asia WGS AF: 0.145 AC: 363 AN: 2521

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 04, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201431046; hg19: chrX-153577132; COSMIC: COSV61049289; COSMIC: COSV61049289;