rs200048692

chrX-154366345-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001110556.2(FLNA):c.1191C>T(p.Ile397=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,211,148 control chromosomes in the GnomAD database, including 1 homozygotes. There are 265 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., 22 hem., cov: 25)
  • Exomes 𝑓: 0.00066 (1 hom. 243 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -3.36

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-154366345-G-A is Benign according to our data. Variant chrX-154366345-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213460.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=3}. Variant chrX-154366345-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000716 (81/113099) while in subpopulation AMR AF= 0.00333 (36/10825). AF 95% confidence interval is 0.00247. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 22 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.1191C>T	p.Ile397=	synonymous_variant	8/48	ENST00000369850.10
FLNA	NM_001456.4	c.1191C>T	p.Ile397=	synonymous_variant	8/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.1191C>T	p.Ile397=	synonymous_variant	8/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 81 AN: 113045 Hom.: 0 Cov.: 25 AF XY: 0.000625 AC XY: 22 AN XY: 35179

Gnomad AFR AF: 0.000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00333

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000600

Gnomad OTH AF: 0.00197

GnomAD3 exomes AF: 0.000275 AC: 50 AN: 181550 Hom.: 0 AF XY: 0.000237 AC XY: 16 AN XY: 67588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000738

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.000896

GnomAD4 exome AF: 0.000662 AC: 727 AN: 1098049 Hom.: 1 Cov.: 33 AF XY: 0.000669 AC XY: 243 AN XY: 363455

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000923

Gnomad4 FIN exome AF: 0.0000495

Gnomad4 NFE exome AF: 0.000781

Gnomad4 OTH exome AF: 0.000955

GnomAD4 genome AF: 0.000716 AC: 81 AN: 113099 Hom.: 0 Cov.: 25 AF XY: 0.000624 AC XY: 22 AN XY: 35243

Gnomad4 AFR AF: 0.000321

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000600

Gnomad4 OTH AF: 0.00195

Alfa AF: 0.000736 Hom.: 7

Bravo AF: 0.00122

EpiCase AF: 0.000763

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 15, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	FLNA: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 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	Aug 10, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2016

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

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.33
Dann	Benign	0.71

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: rs200048692; hg19: chrX-153594713; COSMIC: COSV61043852; COSMIC: COSV61043852;