rs2070819

Variant names:

• chrX-154349931-A-G
• rs2070819
• ENST00000462590.1:n.425T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-154349931-A-G
• chrX-154349931-A-T

Variant summary

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

The ENST00000462590.1(FLNA):​n.425T>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 0.139 in 1,185,740 control chromosomes in the GnomAD database, including 11,012 homozygotes. There are 52,099 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3111 hom., 7209 hem., cov: 25)
  • Exomes 𝑓: 0.13 (7901 hom. 44890 hem.)
• Consequence: FLNA ENST00000462590.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.876
• Publications: 3 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=-0.87).
• BP6: Variant X-154349931-A-G is Benign according to our data. Variant chrX-154349931-A-G is described in ClinVar as Benign. ClinVar VariationId is 674529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.7334-64T>C		intron_variant	Intron 45 of 47	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.7310-64T>C		intron_variant	Intron 44 of 46		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.7334-64T>C		intron_variant	Intron 45 of 47	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes AF: 0.219 AC: 24557 AN: 111905 Hom.: 3098 Cov.: 25

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.00292

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.0552

Gnomad EAS AF: 0.0920

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0675

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.131 AC: 140390 AN: 1073781 Hom.: 7901 Cov.: 27 AF XY: 0.131 AC XY: 44890 AN XY: 342469

African (AFR) AF: 0.491 AC: 12756 AN: 25963

American (AMR) AF: 0.202 AC: 7081 AN: 35050

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 1131 AN: 19239

East Asian (EAS) AF: 0.107 AC: 3215 AN: 30075

South Asian (SAS) AF: 0.174 AC: 9344 AN: 53594

European-Finnish (FIN) AF: 0.147 AC: 5759 AN: 39289

Middle Eastern (MID) AF: 0.0819 AC: 334 AN: 4077

European-Non Finnish (NFE) AF: 0.115 AC: 94174 AN: 821180

Other (OTH) AF: 0.146 AC: 6596 AN: 45314

GnomAD4 genome AF: 0.220 AC: 24620 AN: 111959 Hom.: 3111 Cov.: 25 AF XY: 0.211 AC XY: 7209 AN XY: 34201

African (AFR) AF: 0.479 AC: 14671 AN: 30629

American (AMR) AF: 0.187 AC: 2003 AN: 10715

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 146 AN: 2644

East Asian (EAS) AF: 0.0912 AC: 324 AN: 3554

South Asian (SAS) AF: 0.169 AC: 461 AN: 2733

European-Finnish (FIN) AF: 0.140 AC: 861 AN: 6160

Middle Eastern (MID) AF: 0.0694 AC: 15 AN: 216

European-Non Finnish (NFE) AF: 0.110 AC: 5820 AN: 53107

Other (OTH) AF: 0.209 AC: 317 AN: 1516

Alfa AF: 0.123 Hom.: 4752

Bravo AF: 0.237

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 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.033
DANN	Benign	0.35
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2070819; hg19: chrX-153578299;