NM_001110556.2:c.5251C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001110556.2(FLNA):c.5251C>T(p.Pro1751Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000767 in 1,206,829 control chromosomes in the GnomAD database, including 1 homozygotes. There are 332 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1751L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., 22 hem., cov: 26)

Exomes 𝑓: 0.00077 ( 1 hom. 310 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: 0.541

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062868297).

BP6

Variant X-154354678-G-A is Benign according to our data. Variant chrX-154354678-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213451.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000724 (82/113273) while in subpopulation NFE AF = 0.00105 (56/53280). AF 95% confidence interval is 0.000831. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 22 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.5251C>T	p.Pro1751Ser	missense	Exon 32 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.5227C>T	p.Pro1743Ser	missense	Exon 31 of 47	NP_001447.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLNA	ENST00000369850.10	TSL:1 MANE Select	c.5251C>T	p.Pro1751Ser	missense	Exon 32 of 48	ENSP00000358866.3
FLNA	ENST00000360319.9	TSL:1	c.5227C>T	p.Pro1743Ser	missense	Exon 30 of 46	ENSP00000353467.4
FLNA	ENST00000369856.8	TSL:1	c.5170C>T	p.Pro1724Ser	missense	Exon 31 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes

AF:

0.000715

AC:

AN:

113223

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000961

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000461

Gnomad ASJ

AF:

0.00527

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00131

GnomAD2 exomes

AF:

0.000737

AC:

123

AN:

166980

AF XY:

0.000756

show subpopulations

Gnomad AFR exome

AF:

0.0000890

Gnomad AMR exome

AF:

0.0000756

Gnomad ASJ exome

AF:

0.00419

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000720

GnomAD4 exome

AF:

0.000772

AC:

844

AN:

1093556

Hom.:

Cov.:

AF XY:

0.000861

AC XY:

310

AN XY:

360012

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26345

American (AMR)

AF:

0.000115

AC:

AN:

34799

Ashkenazi Jewish (ASJ)

AF:

0.00492

AC:

AN:

19311

East Asian (EAS)

AF:

0.00

AC:

AN:

30032

South Asian (SAS)

AF:

0.000878

AC:

AN:

53542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39330

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.000697

AC:

586

AN:

840179

Other (OTH)

AF:

0.00137

AC:

AN:

45890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000724

AC:

AN:

113273

Hom.:

Cov.:

AF XY:

0.000621

AC XY:

AN XY:

35421

show subpopulations

African (AFR)

AF:

0.0000959

AC:

AN:

31285

American (AMR)

AF:

0.000460

AC:

AN:

10870

Ashkenazi Jewish (ASJ)

AF:

0.00527

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3571

South Asian (SAS)

AF:

0.00

AC:

AN:

2801

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6361

Middle Eastern (MID)

AF:

0.00922

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00105

AC:

AN:

53280

Other (OTH)

AF:

0.00129

AC:

AN:

1548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.00121

Hom.:

Bravo

AF:

0.000665

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000298

AC:

ESP6500EA

AF:

0.000777

AC:

ExAC

AF:

0.000880

AC:

106

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (6)

Connective tissue disorder (1)

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

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.30

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.73

M_CAP

Benign

0.069

MetaRNN

Benign

0.0063

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

PhyloP100

0.54

PrimateAI

Benign

0.38

PROVEAN

Benign

0.020

REVEL

Benign

0.062

Sift

Benign

0.40

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.088

MVP

0.67

MPC

0.52

ClinPred

0.0025

GERP RS

0.82

PromoterAI

0.043

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.033

gMVP

0.34

Mutation Taster

=295/5

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