rs1557180226

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The ENST00000369856.8(FLNA):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 25)

Consequence

FLNA
ENST00000369856.8 start_lost

Scores

5
8
4

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.22
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 17 pathogenic variants. Next in-frame start position is after 62 codons. Genomic position: 154370981. Lost 0.023 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-154371164-T-C is Pathogenic according to our data. Variant chrX-154371164-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 488068.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNANM_001110556.2 linkc.82A>G p.Met28Val missense_variant Exon 2 of 48 ENST00000369850.10 NP_001104026.1 P21333-1Q60FE5Q6NXF2
FLNANM_001456.4 linkc.82A>G p.Met28Val missense_variant Exon 2 of 47 NP_001447.2 P21333-2Q60FE5Q6NXF2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNAENST00000369850.10 linkc.82A>G p.Met28Val missense_variant Exon 2 of 48 1 NM_001110556.2 ENSP00000358866.3 P21333-1

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
25

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Heterotopia, periventricular, X-linked dominant Pathogenic:1
-
Clinical Genetics Group, University of Otago
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Benign
22
DANN
Benign
0.92
DEOGEN2
Uncertain
0.72
D;.;.;.;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;.;D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Uncertain
0.50
T;D;T;T;D
MetaSVM
Uncertain
0.087
D
MutationAssessor
Benign
1.3
L;.;L;L;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-2.8
D;D;D;D;.
REVEL
Uncertain
0.56
Sift
Uncertain
0.0020
D;D;D;D;.
Sift4G
Benign
0.072
T;D;T;T;D
Polyphen
0.22
B;.;P;P;.
Vest4
0.43
MutPred
0.17
Loss of loop (P = 0.0804);.;Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;
MVP
0.98
MPC
2.2
ClinPred
0.93
D
GERP RS
4.6
Varity_R
0.76
gMVP
0.87

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1557180226; hg19: chrX-153599532; API