rs376726422

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001110556.2(FLNA):c.3611C>T(p.Pro1204Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,209,070 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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. P1204P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000014 ( 0 hom. 5 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.99

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

periventricular nodular heterotopia
Inheritance: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
frontometaphyseal dysplasia 1
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
genetic developmental and epileptic encephalopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
heterotopia, periventricular, X-linked dominant
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Melnick-Needles syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
otopalatodigital syndrome type 2
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
terminal osseous dysplasia-pigmentary defects syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
cardiac valvular dysplasia, X-linked
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
frontometaphyseal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital short bowel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
otopalatodigital syndrome type 1
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked Ehlers-Danlos syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: XL Classification: LIMITED Submitted by: ClinGen

FLNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31711066).

BP6

Variant X-154360184-G-A is Benign according to our data. Variant chrX-154360184-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533565.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.3611C>T	p.Pro1204Leu	missense_variant	Exon 22 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.3611C>T	p.Pro1204Leu	missense_variant	Exon 22 of 47		NP_001447.2	P21333-2Q60FE5Q6NXF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 link	c.3611C>T	p.Pro1204Leu	missense_variant	Exon 22 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000176

AC:

AN:

113505

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.000157

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000446

AC:

AN:

179518

AF XY:

0.0000748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000630

Gnomad NFE exome

AF:

0.0000501

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1095565

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361819

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26365

American (AMR)

AF:

0.0000284

AC:

AN:

35167

Ashkenazi Jewish (ASJ)

AF:

0.0000517

AC:

AN:

19352

East Asian (EAS)

AF:

0.00

AC:

AN:

30160

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54109

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39577

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00000952

AC:

AN:

840721

Other (OTH)

AF:

0.0000217

AC:

AN:

45983

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000176

AC:

AN:

113505

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

35645

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31331

American (AMR)

AF:

0.00

AC:

AN:

10890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3608

South Asian (SAS)

AF:

0.00

AC:

AN:

2847

European-Finnish (FIN)

AF:

0.000157

AC:

AN:

6360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000187

AC:

AN:

53345

Other (OTH)

AF:

0.00

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000152

AC:

ExAC

AF:

0.0000496

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Mar 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P1204L variant (also known as c.3611C>T), located in coding exon 21 of the FLNA gene, results from a C to T substitution at nucleotide position 3611. The proline at codon 1204 is replaced by leucine, an amino acid with similar properties. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (9/201479) total alleles studied, with 6 hemizygote(s) observed. The highest observed frequency was <0.01% (1/5226) of Other alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of FLNA-related otopalatodigital spectrum disorder; however, its contribution to the development of FLNA-related periventricular nodular heterotopia is uncertain. -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant

Benign:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

D;.;.;.;.

FATHMM_MKL

Benign

0.35

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.1

L;.;L;L;.

PhyloP100

4.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.2

N;.;N;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.058

T;.;T;T;.

Sift4G

Uncertain

0.0070

D;D;D;D;D

Polyphen

0.48

P;.;B;B;.

Vest4

0.30

MVP

0.86

MPC

0.62

ClinPred

0.073

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.22

gMVP

0.29

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over