rs2070819

Positions:

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

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001110556.2(FLNA):​c.7334-64T>C variant causes a intron 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 NM_001110556.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.876

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 674529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154349931-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.7334-64T>C		intron_variant		ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.7310-64T>C		intron_variant			NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.7334-64T>C		intron_variant		1	NM_001110556.2	ENSP00000358866

Frequencies

GnomAD3 genomes AF: 0.219 AC: 24557 AN: 111905 Hom.: 3098 Cov.: 25 AF XY: 0.210 AC XY: 7171 AN XY: 34137

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

Gnomad4 AFR exome AF: 0.491

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.146

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

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.0552

Gnomad4 EAS AF: 0.0912

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.209

Alfa AF: 0.123 Hom.: 4217

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.033
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs2070819; hg19: chrX-153578299;