X-154352226-G-C

Variant names:

• chrX-154352226-G-C
• rs1060500717
• NM_001110556.2:c.6724C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001110556.2(FLNA):​c.6724C>G​(p.Arg2242Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.6724C>G	p.Arg2242Gly	missense_variant	Exon 41 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.6700C>G	p.Arg2234Gly	missense_variant	Exon 40 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.6724C>G	p.Arg2242Gly	missense_variant	Exon 41 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1096769 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 2 AN XY: 362655

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D;.;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.016	D;.;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.093	B;.;B;B;.
Vest4		0.80
MutPred		0.60		Loss of sheet (P = 0.0037);.;.;.;.;
MVP		0.99
MPC		0.78
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.79

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: rs1060500717; hg19: chrX-153580594;