rs782637786

chrX-154371169-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BP6

The NM_001110556.2(FLNA):c.77C>T(p.Ala26Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,192,408 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts 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. A26P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 0.000017 (0 hom. 4 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.27

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.32862073).
• BP6: Variant X-154371169-G-A is Benign according to our data. Variant chrX-154371169-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567888.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.77C>T	p.Ala26Val	missense_variant	2/48	ENST00000369850.10
FLNA	NM_001456.4	c.77C>T	p.Ala26Val	missense_variant	2/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.77C>T	p.Ala26Val	missense_variant	2/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.00000914 AC: 1 AN: 109386 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 32442

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000192

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 18 AN: 1083022 Hom.: 0 Cov.: 32 AF XY: 0.0000113 AC XY: 4 AN XY: 353102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000914 AC: 1 AN: 109386 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 32442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000192

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000253 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

FLNA-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2023

The FLNA c.77C>T variant is predicted to result in the amino acid substitution p.Ala26Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-153599537-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.37	T;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.78	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.063	T;T;T
Sift4G	Uncertain	0.052	T;T;T
Polyphen		0.59	P;P;P
Vest4		0.15
MVP		0.89
MPC		1.8
ClinPred		0.26	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.091
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs782637786; hg19: chrX-153599537;