NM_001110556.2:c.1238C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001110556.2(FLNA):c.1238C>T(p.Thr413Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,209,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. T413T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000036 ( 0 hom. 12 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.548

Publications

2 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Melnick-Needles syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
otopalatodigital syndrome type 2
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
terminal osseous dysplasia-pigmentary defects syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, 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: Unknown Classification: LIMITED Submitted by: ClinGen

FLNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21709329).

BP6

Variant X-154366215-G-A is Benign according to our data. Variant chrX-154366215-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211010.

BS2

High Hemizygotes in GnomAdExome4 at 12 XL,AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110556.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.1238C>T	p.Thr413Met	missense	Exon 9 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.1238C>T	p.Thr413Met	missense	Exon 9 of 47	NP_001447.2	P21333-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLNA	ENST00000369850.10	TSL:1 MANE Select	c.1238C>T	p.Thr413Met	missense	Exon 9 of 48	ENSP00000358866.3	P21333-1
FLNA	ENST00000360319.9	TSL:1	c.1238C>T	p.Thr413Met	missense	Exon 8 of 46	ENSP00000353467.4	P21333-2
FLNA	ENST00000369856.8	TSL:1	c.1157C>T	p.Thr386Met	missense	Exon 8 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112243

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000972

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000932

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:

0.000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000500

AC:

AN:

180172

AF XY:

0.0000300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.000135

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1097069

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

362951

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.0000852

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39506

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

842021

Other (OTH)

AF:

0.0000651

AC:

AN:

46080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000107

AC:

AN:

112243

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34437

show subpopulations

African (AFR)

AF:

0.0000972

AC:

AN:

30880

American (AMR)

AF:

0.0000932

AC:

AN:

10735

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2741

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6179

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000151

AC:

AN:

53063

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000130

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.52

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.81

M_CAP

Benign

0.065

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.2

PhyloP100

0.55

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

REVEL

Benign

0.092

Sift

Benign

0.24

Sift4G

Benign

0.10

Polyphen

0.17

Vest4

0.25

MutPred

0.42

Loss of catalytic residue at T413 (P = 0.0172)

MVP

0.76

MPC

0.79

ClinPred

0.017

GERP RS

0.0043

PromoterAI

0.025

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.032

gMVP

0.29

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over