rs113510895

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.6742C>T(p.Leu2248Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00929 in 1,209,725 control chromosomes in the GnomAD database, including 46 homozygotes. There are 3,547 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. L2248L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0068 ( 2 hom., 241 hem., cov: 25)

Exomes 𝑓: 0.0095 ( 44 hom. 3306 hem. )

Consequence

FLNA
NM_001110556.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 4.09

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, 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant X-154352208-G-A is Benign according to our data. Variant chrX-154352208-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00683 (773/113249) while in subpopulation NFE AF = 0.0109 (583/53333). AF 95% confidence interval is 0.0102. There are 2 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 XL,AD,AR 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.6742C>T	p.Leu2248Leu	synonymous	Exon 41 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.6718C>T	p.Leu2240Leu	synonymous	Exon 40 of 47	NP_001447.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLNA	ENST00000369850.10	TSL:1 MANE Select	c.6742C>T	p.Leu2248Leu	synonymous	Exon 41 of 48	ENSP00000358866.3
FLNA	ENST00000360319.9	TSL:1	c.6718C>T	p.Leu2240Leu	synonymous	Exon 39 of 46	ENSP00000353467.4
FLNA	ENST00000369856.8	TSL:1	c.6661C>T	p.Leu2221Leu	synonymous	Exon 40 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes

AF:

0.00683

AC:

773

AN:

113195

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00131

Gnomad AMI

AF:

0.0146

Gnomad AMR

AF:

0.00500

Gnomad ASJ

AF:

0.0106

Gnomad EAS

AF:

0.000277

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00712

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.00587

GnomAD2 exomes

AF:

0.00688

AC:

1222

AN:

177723

AF XY:

0.00666

show subpopulations

Gnomad AFR exome

AF:

0.00158

Gnomad AMR exome

AF:

0.00338

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00853

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00752

GnomAD4 exome

AF:

0.00954

AC:

10460

AN:

1096476

Hom.:

Cov.:

AF XY:

0.00912

AC XY:

3306

AN XY:

362490

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

26371

American (AMR)

AF:

0.00378

AC:

133

AN:

35169

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

223

AN:

19370

East Asian (EAS)

AF:

0.00

AC:

AN:

30183

South Asian (SAS)

AF:

0.000167

AC:

AN:

54029

European-Finnish (FIN)

AF:

0.00871

AC:

346

AN:

39727

Middle Eastern (MID)

AF:

0.00182

AC:

AN:

3842

European-Non Finnish (NFE)

AF:

0.0111

AC:

9324

AN:

841763

Other (OTH)

AF:

0.00850

AC:

391

AN:

46022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

452

904

1356

1808

2260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.00683

AC:

773

AN:

113249

Hom.:

Cov.:

AF XY:

0.00681

AC XY:

241

AN XY:

35389

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

31257

American (AMR)

AF:

0.00499

AC:

AN:

10815

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

AN:

2652

East Asian (EAS)

AF:

0.000278

AC:

AN:

3601

South Asian (SAS)

AF:

0.00

AC:

AN:

2819

European-Finnish (FIN)

AF:

0.00712

AC:

AN:

6318

Middle Eastern (MID)

AF:

0.00922

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0109

AC:

583

AN:

53333

Other (OTH)

AF:

0.00580

AC:

AN:

1553

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00877

Hom.:

Bravo

AF:

0.00676

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

not provided (3)

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over