chrX-154358526-G-A

Position:

chrX-154358526-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The ENST00000369850.10(FLNA):c.4517C>T(p.Thr1506Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,096,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1506T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.00010 ( 0 hom. 47 hem. )

Consequence

FLNA
ENST00000369850.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.90

Variant links:

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]

FLNA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNA. . Gene score misZ 3.7802 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked Ehlers-Danlos syndrome, terminal osseous dysplasia-pigmentary defects syndrome, FG syndrome 2, frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, otopalatodigital syndrome type 2, periventricular nodular heterotopia, otopalatodigital syndrome type 1, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, familial thoracic aortic aneurysm and aortic dissection, congenital short bowel syndrome, frontometaphyseal dysplasia 1, cardiac valvular dysplasia, X-linked.

BS2

High Hemizygotes in GnomAdExome4 at 47 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.4517C>T	p.Thr1506Ile	missense_variant	27/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4 linkuse as main transcript	c.4517C>T	p.Thr1506Ile	missense_variant	27/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.4517C>T	p.Thr1506Ile	missense_variant	27/48	1	NM_001110556.2	ENSP00000358866		P21333-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000276

AC:

AN:

180999

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

67265

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

113

AN:

1096525

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

362155

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 05, 2015

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 19, 2023

The FLNA c.4517C>T; p.Thr1506Ile variant (rs797045579), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 211017). This variant is found in the general population with an overall allele frequency of 0.0028% (5/180999 alleles, including 2 hemizygotes) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.526). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Melnick-Needles syndrome;C0262436:Cardiac valvular dysplasia, X-linked;C0265251:Oto-palato-digital syndrome, type I;C1844696:Oto-palato-digital syndrome, type II;C1845902:FG syndrome 2;C1846129:Terminal osseous dysplasia-pigmentary defects syndrome;C1848213:Heterotopia, periventricular, X-linked dominant;C2746068:Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked;C4281559:Frontometaphyseal dysplasia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 16, 2022

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 0.006% [5/81122], including 2 hemizygotes; https://gnomad.broadinstitute.org/variant/X-153586894-G-A?dataset=gnomad_r2_1), and in ClinVar (Variation ID:211017). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.0016

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.;.;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D;.;D;D

M_CAP

Benign

0.064

MetaRNN

Uncertain

0.62

D;D;D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.5

M;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.3

D;.;D;D;.

REVEL

Uncertain

0.53

Sift

Benign

0.17

T;.;T;T;.

Sift4G

Benign

0.086

T;T;T;T;D

Polyphen

0.011

B;.;P;P;.

Vest4

0.51

MVP

0.90

MPC

0.60

ClinPred

0.43

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.45

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over