rs137853319

chrX-154359839-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):c.3872C>T(p.Pro1291Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,209,459 control chromosomes in the GnomAD database, including 2 homozygotes. There are 80 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1291P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 16 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (2 hom. 64 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 2.42

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP6: Variant X-154359839-G-A is Benign according to our data. Variant chrX-154359839-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 11774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154359839-G-A is described in Lovd as [Likely_benign]. Variant chrX-154359839-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000276 (31/112457) while in subpopulation SAS AF= 0.00183 (5/2726). AF 95% confidence interval is 0.000932. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.3872C>T	p.Pro1291Leu	missense_variant	23/48	ENST00000369850.10
FLNA	NM_001456.4	c.3872C>T	p.Pro1291Leu	missense_variant	23/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.3872C>T	p.Pro1291Leu	missense_variant	23/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 31 AN: 112404 Hom.: 0 Cov.: 24 AF XY: 0.000463 AC XY: 16 AN XY: 34550

Gnomad AFR AF: 0.0000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00149

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00183

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000271 AC: 49 AN: 180492 Hom.: 1 AF XY: 0.000356 AC XY: 24 AN XY: 67370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.000130 AC: 143 AN: 1097002 Hom.: 2 Cov.: 33 AF XY: 0.000176 AC XY: 64 AN XY: 362970

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000312

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.000101

Gnomad4 NFE exome AF: 0.0000665

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000276 AC: 31 AN: 112457 Hom.: 0 Cov.: 24 AF XY: 0.000462 AC XY: 16 AN XY: 34613

Gnomad4 AFR AF: 0.0000645

Gnomad4 AMR AF: 0.00149

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00183

Gnomad4 FIN AF: 0.000161

Gnomad4 NFE AF: 0.0000942

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000404 Hom.: 2

Bravo AF: 0.000185

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000153 AC: 1

ExAC AF: 0.000281 AC: 34

EpiCase AF: 0.000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2020	This variant is associated with the following publications: (PMID: 16299064, 28133863, 23873601, 25167861, 17632775, 23871722) -
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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FLNA: BP4, BS2 -

FG syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 15, 2007

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2017

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

Jan 15, 2024

- -

FLNA-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.;.
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Uncertain	0.045	D
MutationAssessor	Benign	1.0	L;.;L;L;.
MutationTaster	Benign	0.00024	A;A;A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	D;.;D;D;.
REVEL	Uncertain	0.51
Sift	Benign	0.079	T;.;D;D;.
Sift4G	Uncertain	0.035	D;D;D;D;T
Polyphen		0.066	B;.;P;P;.
Vest4		0.27
MVP		0.95
MPC		0.57
ClinPred		0.051	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.77

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: rs137853319; hg19: chrX-153588207; COSMIC: COSV100774364; COSMIC: COSV100774364;