rs80338841

Variant names:

• chrX-154364625-G-A
• rs80338841
• NM_001110556.2:c.1923C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001110556.2(FLNA):​c.1923C>T​(p.Gly641Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 O:1
• Conservation: PhyloP100: -0.629

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-154364625-G-A is Pathogenic according to our data. Variant chrX-154364625-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11770.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, not_provided=1}. Variant chrX-154364625-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.1923C>T	p.Gly641Gly	synonymous_variant	Exon 13 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.1923C>T	p.Gly641Gly	synonymous_variant	Exon 13 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.1923C>T	p.Gly641Gly	synonymous_variant	Exon 13 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000273 AC: 3 AN: 1097512 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Oct 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant creates an upstream cryptic splice donor site and leads to abnormal gene splicing in a gene for which loss-of-function is a known mechanism of disease (Hehr et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16299064, 26582918, 27535533) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLNA: PM2:Supporting, PP3, PS3:Supporting, PS4:Supporting -

FLNA-related disorder Pathogenic:1

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FLNA c.1923C>T variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the hemizygous state in a male patient with periventricular nodular heterotopia (PVNH) and in his clinically asymptomatic mother who also had PVNH on MRI (Hehr et al. 2006. PubMed ID: 16299064). cDNA sequencing indicated this variant impacts mRNA splicing (Hehr et al. 2006. PubMed ID: 16299064). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

FLNA-related periventricular nodular heterotopia Pathogenic:1

Jan 29, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FLNA c.1923C>T (p.Gly641) variant is a synonymous variant that creates a novel donor splice site and that has been reported in one study in which it was found in a hemizygous state in a male child with periventricular nodular heterotopia, dysmorphic facial features, and severe constipation (Hehr et al. 2006). The variant was also identified in a heterozygous state in the proband's clinically unaffected mother who was later found to have periventricular nodular heterotopia on brain MRI performed after detection of this variant in her child. PCR amplification of cDNA from cultured lymphocytes from the proband, unaffected mother, and an unaffected brother who did not carry the variant, revealed a normal length product for all three individuals in addition to a smaller product observed for the proband and mother. This smaller product was a result of alternative splicing using the newly created donor splice site, which causes loss of the 3' segment of exon 13 resulting in a frameshift and premature stop codon at residue 681. The c.1923C>T variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence in the literature and application of the ACMG criteria, the c.1923C>T variant is classified as pathogenic for FLNA-related periventricular nodular heterotopia. -

Heterotopia, periventricular, X-linked dominant Pathogenic:1

Aug 15, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Oct 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 641 of the FLNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FLNA protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of FLNA-related conditions (PMID: 16299064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11770). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16299064). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiac valvular dysplasia, X-linked Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.92		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80338841; hg19: chrX-153592993; COSMIC: COSV61040235; COSMIC: COSV61040235;