rs371600068

chrX-154366817-C-AchrX-154366817-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001110556.2(FLNA):c.902G>T(p.Arg301Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,210,174 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R301W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000030 (0 hom. 13 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.56

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.20354089).
• BP6: Variant X-154366817-C-A is Benign according to our data. Variant chrX-154366817-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405457.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.902G>T	p.Arg301Leu	missense_variant	6/48	ENST00000369850.10
FLNA	NM_001456.4	c.902G>T	p.Arg301Leu	missense_variant	6/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.902G>T	p.Arg301Leu	missense_variant	6/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112711 Hom.: 0 Cov.: 24 AF XY: 0.0000287 AC XY: 1 AN XY: 34853

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000362

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000334 AC: 6 AN: 179873 Hom.: 0 AF XY: 0.0000300 AC XY: 2 AN XY: 66651

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 33 AN: 1097463 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 13 AN XY: 362951

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000178

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112711 Hom.: 0 Cov.: 24 AF XY: 0.0000287 AC XY: 1 AN XY: 34853

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000362

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ESP6500AA AF: 0.000272 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000413 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 08, 2017

- -

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

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D;.;.;.;.
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.87	D;D;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.2	L;.;L;L;.
MutationTaster	Benign	0.83	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N;.;N;N;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.022	D;.;D;D;.
Sift4G	Uncertain	0.026	D;D;D;D;D
Polyphen		0.20	B;.;B;B;.
Vest4		0.23
MVP		0.89
MPC		0.66
ClinPred		0.19	T
GERP RS		5.2
Varity_R		0.28
gMVP		0.61

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: rs371600068; hg19: chrX-153595185;