X-154348865-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_001110556.2(FLNA):c.7928G>A(p.Arg2643His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,206,783 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2643C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.1286434).
• BP6: Variant X-154348865-C-T is Benign according to our data. Variant chrX-154348865-C-T is described in ClinVar as [Benign]. Clinvar id is 1020536.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.7928G>A	p.Arg2643His	missense_variant	48/48	ENST00000369850.10
FLNA	NM_001456.4	c.7904G>A	p.Arg2635His	missense_variant	47/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.7928G>A	p.Arg2643His	missense_variant	48/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112114 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34312

Gnomad AFR AF: 0.0000324

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000113 AC: 2 AN: 176671 Hom.: 0 AF XY: 0.0000312 AC XY: 2 AN XY: 64187

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1094669 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 2 AN XY: 360845

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000521

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112114 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34312

Gnomad4 AFR AF: 0.0000324

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: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

Nov 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Benign	0.86
DEOGEN2	Benign	0.35	T;.;.;.;.
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.15	N;.;.;.;.
MutationTaster	Benign	0.87	D;D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.6	N;.;N;N;.
REVEL	Benign	0.19
Sift	Benign	0.50	T;.;T;T;.
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.0010	B;.;B;B;.
Vest4		0.084
MutPred		0.65		Loss of sheet (P = 0.0817);.;.;.;.;
MVP		0.61
MPC		0.64
ClinPred		0.17	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.19

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: rs782641074; hg19: chrX-153577233; COSMIC: COSV61038096; COSMIC: COSV61038096;