rs200835571

chrX-154357513-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001110556.2(FLNA):c.4866C>T(p.Tyr1622=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000874 in 1,209,716 control chromosomes in the GnomAD database, including 3 homozygotes. There are 368 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 0.00071 (1 hom., 15 hem., cov: 25)
  • Exomes 𝑓: 0.00089 (2 hom. 353 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.80

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-154357513-G-A is Benign according to our data. Variant chrX-154357513-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 190196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154357513-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000707 (80/113219) while in subpopulation SAS AF= 0.0032 (9/2810). AF 95% confidence interval is 0.00167. There are 1 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.4866C>T	p.Tyr1622=	synonymous_variant	29/48	ENST00000369850.10
FLNA	NM_001456.4	c.4866C>T	p.Tyr1622=	synonymous_variant	29/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.4866C>T	p.Tyr1622=	synonymous_variant	29/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.000707 AC: 80 AN: 113166 Hom.: 1 Cov.: 25 AF XY: 0.000425 AC XY: 15 AN XY: 35308

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000277

Gnomad ASJ AF: 0.00150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00319

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000764 AC: 138 AN: 180618 Hom.: 1 AF XY: 0.000894 AC XY: 60 AN XY: 67148

Gnomad AFR exome AF: 0.000162

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00210

Gnomad FIN exome AF: 0.000253

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.000451

GnomAD4 exome AF: 0.000891 AC: 977 AN: 1096497 Hom.: 2 Cov.: 32 AF XY: 0.000975 AC XY: 353 AN XY: 361981

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00274

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00253

Gnomad4 FIN exome AF: 0.000248

Gnomad4 NFE exome AF: 0.000856

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000707 AC: 80 AN: 113219 Hom.: 1 Cov.: 25 AF XY: 0.000424 AC XY: 15 AN XY: 35371

Gnomad4 AFR AF: 0.0000320

Gnomad4 AMR AF: 0.000277

Gnomad4 ASJ AF: 0.00150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00320

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00135 Hom.: 12

Bravo AF: 0.000631

EpiCase AF: 0.00142

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Sep 27, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 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	Genetic Services Laboratory, University of Chicago	Apr 16, 2018	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 17, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2015

This alteration is classified as likely 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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.049
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs200835571; hg19: chrX-153585881; COSMIC: COSV61039914; COSMIC: COSV61039914;