rs2070817

Positions:

• chrX-154368109-C-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.374-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,208,246 control chromosomes in the GnomAD database, including 1,832 homozygotes. There are 24,923 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (116 hom., 1415 hem., cov: 24)
  • Exomes 𝑓: 0.064 (1716 hom. 23508 hem.)
• Consequence: FLNA NM_001110556.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.295

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=-0.88).
• BP6: Variant X-154368109-C-T is Benign according to our data. Variant chrX-154368109-C-T is described in ClinVar as [Benign]. Clinvar id is 93758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154368109-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.374-19G>A		intron_variant		ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.374-19G>A		intron_variant			NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.374-19G>A		intron_variant		1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 4727 AN: 111282 Hom.: 109 Cov.: 24 AF XY: 0.0421 AC XY: 1410 AN XY: 33468

Gnomad AFR AF: 0.00925

Gnomad AMI AF: 0.00595

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0889

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0369

GnomAD3 exomes AF: 0.0504 AC: 9072 AN: 180060 Hom.: 200 AF XY: 0.0553 AC XY: 3703 AN XY: 67018

Gnomad AFR exome AF: 0.00824

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.00694

Gnomad SAS exome AF: 0.0904

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.0598

Gnomad OTH exome AF: 0.0435

GnomAD4 exome AF: 0.0637 AC: 69895 AN: 1096911 Hom.: 1716 Cov.: 32 AF XY: 0.0648 AC XY: 23508 AN XY: 362829

Gnomad4 AFR exome AF: 0.00712

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.0301

Gnomad4 EAS exome AF: 0.00569

Gnomad4 SAS exome AF: 0.0898

Gnomad4 FIN exome AF: 0.0964

Gnomad4 NFE exome AF: 0.0678

Gnomad4 OTH exome AF: 0.0565

GnomAD4 genome AF: 0.0426 AC: 4746 AN: 111335 Hom.: 116 Cov.: 24 AF XY: 0.0422 AC XY: 1415 AN XY: 33531

Gnomad4 AFR AF: 0.00923

Gnomad4 AMR AF: 0.0151

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.0892

Gnomad4 FIN AF: 0.0877

Gnomad4 NFE AF: 0.0631

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0540 Hom.: 464

Bravo AF: 0.0353

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2014	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

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	-0.88
CADD	Benign	4.8
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2070817; hg19: chrX-153596477;