rs782426283

chrX-154359317-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001110556.2(FLNA):c.4232C>T(p.Ser1411Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,209,922 control chromosomes in the GnomAD database, including 1 homozygotes. There are 125 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). Synonymous variant affecting the same amino acid position (i.e. S1411S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.00021 (1 hom. 120 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: 1.16

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.038050085).
• BP6: Variant X-154359317-G-A is Benign according to our data. Variant chrX-154359317-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435207.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chrX-154359317-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000621 (7/112702) while in subpopulation SAS AF= 0.00108 (3/2788). AF 95% confidence interval is 0.000292. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.4232C>T	p.Ser1411Leu	missense_variant	25/48	ENST00000369850.10
FLNA	NM_001456.4	c.4232C>T	p.Ser1411Leu	missense_variant	25/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.4232C>T	p.Ser1411Leu	missense_variant	25/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000621 AC: 7 AN: 112702 Hom.: 0 Cov.: 24 AF XY: 0.000143 AC XY: 5 AN XY: 34848

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000359 AC: 65 AN: 181241 Hom.: 1 AF XY: 0.000460 AC XY: 31 AN XY: 67461

Gnomad AFR exome AF: 0.0000809

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00325

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000213 AC: 234 AN: 1097220 Hom.: 1 Cov.: 33 AF XY: 0.000330 AC XY: 120 AN XY: 363132

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00392

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.0000621 AC: 7 AN: 112702 Hom.: 0 Cov.: 24 AF XY: 0.000143 AC XY: 5 AN XY: 34848

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00108

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000298 Hom.: 1

Bravo AF: 0.0000945

ExAC AF: 0.000487 AC: 59

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2017	- -

Heterotopia, periventricular, X-linked dominant Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Sep 26, 2019

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2019

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 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2020

This variant is associated with the following publications: (PMID: 20598277, 28454995) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.;.
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.038	T;T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	M;.;M;M;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.2	D;.;D;D;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;.;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.95	P;.;P;P;.
Vest4		0.24
MutPred		0.53		Gain of catalytic residue at S1411 (P = 0.0016);.;Gain of catalytic residue at S1411 (P = 0.0016);Gain of catalytic residue at S1411 (P = 0.0016);.;
MVP		0.90
MPC		0.68
ClinPred		0.095	T
GERP RS		5.5
Varity_R		0.51
gMVP		0.69

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: rs782426283; hg19: chrX-153587685;