rs781919390

chrX-154352456-T-C

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.6503-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,210,193 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 69 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 0.00015 (0 hom. 69 hem.)
• Consequence: FLNA NM_001110556.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002352
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.13

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=-0.93).
• BP6: Variant X-154352456-T-C is Benign according to our data. Variant chrX-154352456-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 465013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154352456-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000148 (162/1097431) while in subpopulation MID AF= 0.000969 (4/4130). AF 95% confidence interval is 0.000398. There are 0 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.6503-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000369850.10
FLNA	NM_001456.4	c.6479-9A>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.6503-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000444 AC: 5 AN: 112705 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34899

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000360

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000248 AC: 45 AN: 181367 Hom.: 0 AF XY: 0.000341 AC XY: 23 AN XY: 67403

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000892

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000897

GnomAD4 exome AF: 0.000148 AC: 162 AN: 1097431 Hom.: 0 Cov.: 33 AF XY: 0.000190 AC XY: 69 AN XY: 363141

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000326

GnomAD4 genome AF: 0.0000443 AC: 5 AN: 112762 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34966

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000360

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000753

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 2

Bravo AF: 0.000162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2020	- -

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 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.90
Dann	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.050
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: rs781919390; hg19: chrX-153580824;