rs782007408

chrX-154366597-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):c.1030G>A(p.Val344Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000801 in 1,210,812 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V344V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., 4 hem., cov: 25)
  • Exomes 𝑓: 0.000083 (0 hom. 20 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.67

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.049929112).
• BP6: Variant X-154366597-C-T is Benign according to our data. Variant chrX-154366597-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 282366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000829 (91/1097921) while in subpopulation AMR AF= 0.0019 (67/35206). AF 95% confidence interval is 0.00154. There are 0 homozygotes in gnomad4_exome. There are 20 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.1030G>A	p.Val344Ile	missense_variant	7/48	ENST00000369850.10
FLNA	NM_001456.4	c.1030G>A	p.Val344Ile	missense_variant	7/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.1030G>A	p.Val344Ile	missense_variant	7/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 6 AN: 112891 Hom.: 0 Cov.: 25 AF XY: 0.000114 AC XY: 4 AN XY: 35037

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000278

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000352 AC: 64 AN: 181599 Hom.: 0 AF XY: 0.000177 AC XY: 12 AN XY: 67629

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.0000829 AC: 91 AN: 1097921 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 20 AN XY: 363311

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000531 AC: 6 AN: 112891 Hom.: 0 Cov.: 25 AF XY: 0.000114 AC XY: 4 AN XY: 35037

Gnomad4 AFR AF: 0.0000322

Gnomad4 AMR AF: 0.000278

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.000306 AC: 37

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 17, 2016

- -

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

Dec 11, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2020

- -

FLNA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

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	0.32
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Uncertain	0.49	T;.;.;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.050	T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.3	M;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.91	N;.;N;N;.
REVEL	Uncertain	0.50
Sift	Benign	0.11	T;.;T;T;.
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.99	D;.;D;D;.
Vest4		0.32
MVP		0.87
MPC		1.2
ClinPred		0.13	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.30
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs782007408; hg19: chrX-153594965;