rs182894587

chrX-154353943-G-A

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.5658C>T(p.Phe1886=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000834 in 1,211,002 control chromosomes in the GnomAD database, including 1 homozygotes. There are 34 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 0.00017 (0 hom., 3 hem., cov: 26)
  • Exomes 𝑓: 0.000075 (1 hom. 31 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.50

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=-0.6).
• BP6: Variant X-154353943-G-A is Benign according to our data. Variant chrX-154353943-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000168 (19/113041) while in subpopulation EAS AF= 0.00473 (17/3595). AF 95% confidence interval is 0.00301. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.5658C>T	p.Phe1886=	synonymous_variant	35/48	ENST00000369850.10
FLNA	NM_001456.4	c.5634C>T	p.Phe1878=	synonymous_variant	34/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.5658C>T	p.Phe1886=	synonymous_variant	35/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.000168 AC: 19 AN: 112987 Hom.: 0 Cov.: 26 AF XY: 0.0000854 AC XY: 3 AN XY: 35123

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000927

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00471

Gnomad SAS AF: 0.000358

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000380 AC: 69 AN: 181609 Hom.: 1 AF XY: 0.000355 AC XY: 24 AN XY: 67601

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00509

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000747 AC: 82 AN: 1097961 Hom.: 1 Cov.: 32 AF XY: 0.0000853 AC XY: 31 AN XY: 363349

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00238

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.000108

GnomAD4 genome AF: 0.000168 AC: 19 AN: 113041 Hom.: 0 Cov.: 26 AF XY: 0.0000853 AC XY: 3 AN XY: 35187

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000926

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00473

Gnomad4 SAS AF: 0.000359

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Nov 10, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	11
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs182894587; hg19: chrX-153582311;