rs782239678

chrX-154361775-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):c.2839G>A(p.Val947Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000045 in 1,200,657 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000046 (0 hom. 30 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.762

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.0450477).
• BP6: Variant X-154361775-C-T is Benign according to our data. Variant chrX-154361775-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 574436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000459 (50/1089997) while in subpopulation SAS AF= 0.000723 (39/53945). AF 95% confidence interval is 0.000543. There are 0 homozygotes in gnomad4_exome. There are 30 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.2839G>A	p.Val947Ile	missense_variant	20/48	ENST00000369850.10
FLNA	NM_001456.4	c.2839G>A	p.Val947Ile	missense_variant	20/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.2839G>A	p.Val947Ile	missense_variant	20/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000362 AC: 4 AN: 110605 Hom.: 0 Cov.: 23 AF XY: 0.0000305 AC XY: 1 AN XY: 32815

Gnomad AFR AF: 0.0000329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000953

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000398

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000190

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000882 AC: 16 AN: 181324 Hom.: 0 AF XY: 0.000134 AC XY: 9 AN XY: 67412

Gnomad AFR exome AF: 0.0000809

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000629

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000459 AC: 50 AN: 1089997 Hom.: 0 Cov.: 31 AF XY: 0.0000843 AC XY: 30 AN XY: 355709

Gnomad4 AFR exome AF: 0.0000381

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000723

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome AF: 0.0000361 AC: 4 AN: 110660 Hom.: 0 Cov.: 23 AF XY: 0.0000304 AC XY: 1 AN XY: 32880

Gnomad4 AFR AF: 0.0000329

Gnomad4 AMR AF: 0.0000952

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000399

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000190

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.0000151

ExAC AF: 0.0000993 AC: 12

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 04, 2019

- -

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

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.010
Dann	Benign	0.88
DEOGEN2	Benign	0.41	T;.;.;.;.
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.85	T;T;.;T;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.045	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.46	N;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.46	N;.;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.32	T;.;T;T;.
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		0.10	B;.;B;B;.
Vest4		0.12
MutPred		0.47		Loss of catalytic residue at V947 (P = 0.0137);.;Loss of catalytic residue at V947 (P = 0.0137);Loss of catalytic residue at V947 (P = 0.0137);.;
MVP		0.77
MPC		0.47
ClinPred		0.0097	T
GERP RS		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782239678; hg19: chrX-153590143; COSMIC: COSV61043731; COSMIC: COSV61043731;