rs782580317

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP2PP3BP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.1693C>T(p.Pro565Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000019 in 1,209,881 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000018 ( 0 hom. 7 hem. )

Consequence

FLNA
NM_001110556.2 missense, splice_region

Scores

Splicing: ADA: 0.0001479

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 8.08

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNA

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

BP6

Variant X-154364956-G-A is Benign according to our data. Variant chrX-154364956-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 569957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000182 (20/1097377) while in subpopulation EAS AF= 0.000497 (15/30206). AF 95% confidence interval is 0.000305. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.1693C>T	p.Pro565Ser	missense_variant, splice_region_variant	12/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.1693C>T	p.Pro565Ser	missense_variant, splice_region_variant	12/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.1693C>T	p.Pro565Ser	missense_variant, splice_region_variant	12/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112504

Hom.:

Cov.:

AF XY:

0.0000577

AC XY:

AN XY:

34648

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:

0.000560

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000657

GnomAD3 exomes

AF:

0.0000772

AC:

AN:

181275

Hom.:

AF XY:

0.0000890

AC XY:

AN XY:

67419

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000812

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1097377

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

363219

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000497

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112504

Hom.:

Cov.:

AF XY:

0.0000577

AC XY:

AN XY:

34648

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000560

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000657

Bravo

AF:

0.0000151

ExAC

AF:

0.0000578

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2023

- -

FLNA-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Uncertain

0.11

Cadd

Uncertain

Dann

Benign

0.40

DEOGEN2

Pathogenic

0.90

D;.;.;.;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

1.0

D;D;.;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.;H;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.6

D;.;D;D;.

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;.;D;D;.

Sift4G

Uncertain

0.022

D;D;D;D;D

Polyphen

0.87

P;.;P;P;.

Vest4

0.54

MutPred

0.86

Gain of relative solvent accessibility (P = 0.0479);.;Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);.;

MVP

0.97

MPC

1.4

ClinPred

0.94

GERP RS

3.5

Varity_R

0.93

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.026

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over