rs121908415
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The ENST00000252699.7(ACTN4):āc.763A>Gā(p.Lys255Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Consequence
ACTN4
ENST00000252699.7 missense
ENST00000252699.7 missense
Scores
12
5
1
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
ACTN4 (HGNC:166): (actinin alpha 4) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
In a domain Calponin-homology (CH) 2 (size 106) in uniprot entity ACTN4_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in ENST00000252699.7
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN4. . Gene score misZ 4.1552 (greater than the threshold 3.09). Trascript score misZ 5.6825 (greater than threshold 3.09). GenCC has associacion of gene with familial idiopathic steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 19-38710286-A-G is Pathogenic according to our data. Variant chr19-38710286-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38710286-A-G is described in UniProt as null.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTN4 | NM_004924.6 | c.763A>G | p.Lys255Glu | missense_variant | 8/21 | ENST00000252699.7 | NP_004915.2 | |
LOC107985291 | XR_001753937.2 | n.170-8122T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTN4 | ENST00000252699.7 | c.763A>G | p.Lys255Glu | missense_variant | 8/21 | 1 | NM_004924.6 | ENSP00000252699 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 33
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GnomAD4 exome Cov.: 32
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74320
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Focal segmental glomerulosclerosis 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 19, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 23, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ACTN4 protein function (PMID: 10700177, 22351778). This variant has been observed in individual(s) with focal segmental glomerulosclerosis (PMID: 10700177). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Lys228Glu in the literature. ClinVar contains an entry for this variant (Variation ID: 5420). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 255 of the ACTN4 protein (p.Lys255Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of ubiquitination at K255 (P = 0.0183);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at