rs56102764

chrX-154354678-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.5251C>T(p.Pro1751Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000767 in 1,206,829 control chromosomes in the GnomAD database, including 1 homozygotes. There are 332 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1751L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., 22 hem., cov: 26)
  • Exomes 𝑓: 0.00077 (1 hom. 310 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 0.541

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=0.0062868297).
• BP6: Variant X-154354678-G-A is Benign according to our data. Variant chrX-154354678-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213451.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=5, Uncertain_significance=1}. Variant chrX-154354678-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000724 (82/113273) while in subpopulation NFE AF= 0.00105 (56/53280). AF 95% confidence interval is 0.000831. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 26. 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.5251C>T	p.Pro1751Ser	missense_variant	32/48	ENST00000369850.10
FLNA	NM_001456.4	c.5227C>T	p.Pro1743Ser	missense_variant	31/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.5251C>T	p.Pro1751Ser	missense_variant	32/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.000715 AC: 81 AN: 113223 Hom.: 0 Cov.: 26 AF XY: 0.000622 AC XY: 22 AN XY: 35361

Gnomad AFR AF: 0.0000961

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000461

Gnomad ASJ AF: 0.00527

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.000737 AC: 123 AN: 166980 Hom.: 1 AF XY: 0.000756 AC XY: 43 AN XY: 56876

Gnomad AFR exome AF: 0.0000890

Gnomad AMR exome AF: 0.0000756

Gnomad ASJ exome AF: 0.00419

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000676

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000720

GnomAD4 exome AF: 0.000772 AC: 844 AN: 1093556 Hom.: 1 Cov.: 32 AF XY: 0.000861 AC XY: 310 AN XY: 360012

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00492

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000878

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000697

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.000724 AC: 82 AN: 113273 Hom.: 0 Cov.: 26 AF XY: 0.000621 AC XY: 22 AN XY: 35421

Gnomad4 AFR AF: 0.0000959

Gnomad4 AMR AF: 0.000460

Gnomad4 ASJ AF: 0.00527

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.00129

Alfa AF: 0.00122 Hom.: 54

Bravo AF: 0.000665

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000298 AC: 1

ESP6500EA AF: 0.000777 AC: 5

ExAC AF: 0.000880 AC: 106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 30, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2023	Variant summary: FLNA c.5251C>T (p.Pro1751Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 166980 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes and 24 hemizygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3200 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNA causing Periventricular Nodular Heterotopia phenotype (3.1e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.5251C>T in individuals affected with Periventricular Nodular Heterotopia and no experimental evidence demonstrating its impact on protein function have been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=9) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	12
Dann	Benign	0.79
DEOGEN2	Benign	0.30	T;.;.;.;.
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.73	T;T;.;T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.0063	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.020	N;.;N;N;.
REVEL	Benign	0.062
Sift	Benign	0.40	T;.;T;T;.
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.0	B;.;B;B;.
Vest4		0.088
MVP		0.67
MPC		0.52
ClinPred		0.0025	T
GERP RS		0.82
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.033
gMVP		0.34

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: rs56102764; hg19: chrX-153583046;