rs112379782

chrX-154358437-C-GchrX-154358437-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):c.4598+8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,209,677 control chromosomes in the GnomAD database, including 48 homozygotes. There are 742 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., 345 hem., cov: 25)
  • Exomes 𝑓: 0.0013 (30 hom. 397 hem.)
• Consequence: FLNA NM_001110556.2 splice_region, intron
• Scores: Splicing: ADA: 0.00006893
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.303

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=-0.76).
• BP6: Variant X-154358437-C-G is Benign according to our data. Variant chrX-154358437-C-G is described in ClinVar as [Benign]. Clinvar id is 129074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154358437-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1295/112001) while in subpopulation AFR AF= 0.0392 (1209/30816). AF 95% confidence interval is 0.0374. There are 18 homozygotes in gnomad4. There are 345 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.4598+8G>C		splice_region_variant, intron_variant		ENST00000369850.10
FLNA	NM_001456.4	c.4598+8G>C		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.4598+8G>C		splice_region_variant, intron_variant		1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1291 AN: 111947 Hom.: 18 Cov.: 25 AF XY: 0.0101 AC XY: 344 AN XY: 34105

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00627

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00791

GnomAD3 exomes AF: 0.00337 AC: 610 AN: 181203 Hom.: 16 AF XY: 0.00197 AC XY: 133 AN XY: 67467

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000863

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00133 AC: 1458 AN: 1097676 Hom.: 30 Cov.: 32 AF XY: 0.00109 AC XY: 397 AN XY: 363240

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.00301

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000923

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000831

Gnomad4 OTH exome AF: 0.00302

GnomAD4 genome AF: 0.0116 AC: 1295 AN: 112001 Hom.: 18 Cov.: 25 AF XY: 0.0101 AC XY: 345 AN XY: 34169

Gnomad4 AFR AF: 0.0392

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00781

Alfa AF: 0.000698 Hom.: 3

Bravo AF: 0.0142

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 04, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -

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

Invitae

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.63
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs112379782; hg19: chrX-153586805;