dbSNP rs34439033: FLNA:p.Ser1411Ser (chrX-154359316-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001110556.2(FLNA):c.4233G>A(p.Ser1411Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,210,037 control chromosomes in the GnomAD database, including 7 homozygotes. There are 261 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., 72 hem., cov: 25)

Exomes 𝑓: 0.00057 ( 6 hom. 189 hem. )

Consequence

FLNA
NM_001110556.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.82

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant X-154359316-C-T is Benign according to our data. Variant chrX-154359316-C-T is described in ClinVar as Benign. ClinVar VariationId is 129073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.82 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00281 (317/112756) while in subpopulation AFR AF = 0.00909 (283/31120). AF 95% confidence interval is 0.00822. There are 1 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 72 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.4233G>A	p.Ser1411Ser	synonymous	Exon 25 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.4233G>A	p.Ser1411Ser	synonymous	Exon 25 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.4233G>A	p.Ser1411Ser	synonymous	Exon 25 of 48	ENSP00000358866.3	P21333-1
FLNA	ENST00000360319.9	TSL:1	c.4233G>A	p.Ser1411Ser	synonymous	Exon 24 of 46	ENSP00000353467.4	P21333-2
FLNA	ENST00000369856.8	TSL:1	c.4152G>A	p.Ser1384Ser	synonymous	Exon 24 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes

AF:

0.00278

AC:

313

AN:

112706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00898

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000930

Gnomad ASJ

AF:

0.00526

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000169

Gnomad OTH

AF:

0.000658

GnomAD2 exomes

AF:

0.00104

AC:

189

AN:

181247

AF XY:

0.000697

show subpopulations

Gnomad AFR exome

AF:

0.00931

Gnomad AMR exome

AF:

0.000840

Gnomad ASJ exome

AF:

0.00309

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.00202

GnomAD4 exome

AF:

0.000568

AC:

623

AN:

1097281

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

189

AN XY:

363191

show subpopulations

African (AFR)

AF:

0.00966

AC:

255

AN:

26401

American (AMR)

AF:

0.00105

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00335

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000923

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39668

Middle Eastern (MID)

AF:

0.00338

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000181

AC:

152

AN:

842048

Other (OTH)

AF:

0.00206

AC:

AN:

46083

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00281

AC:

317

AN:

112756

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

AN XY:

34906

show subpopulations

African (AFR)

AF:

0.00909

AC:

283

AN:

31120

American (AMR)

AF:

0.000929

AC:

AN:

10761

Ashkenazi Jewish (ASJ)

AF:

0.00526

AC:

AN:

2662

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.00

AC:

AN:

2769

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000169

AC:

AN:

53213

Other (OTH)

AF:

0.000651

AC:

AN:

1537

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00291

Hom.:

Bravo

AF:

0.00314

EpiCase

AF:

0.000327

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

FLNA-related disorder (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

-0.65

CADD

Benign

0.057

(source)

DANN

Benign

0.50

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over