rs146493523
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004924.6(ACTN4):c.2679C>T(p.Pro893=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,612,754 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00037 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00022 ( 2 hom. )
Consequence
ACTN4
NM_004924.6 synonymous
NM_004924.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.75
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
?
Variant 19-38729375-C-T is Benign according to our data. Variant chr19-38729375-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 585364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000375 (57/152186) while in subpopulation EAS AF= 0.00639 (33/5168). AF 95% confidence interval is 0.00467. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High AC in GnomAd at 57 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN4 | NM_004924.6 | c.2679C>T | p.Pro893= | synonymous_variant | 21/21 | ENST00000252699.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN4 | ENST00000252699.7 | c.2679C>T | p.Pro893= | synonymous_variant | 21/21 | 1 | NM_004924.6 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000375 AC: 57AN: 152068Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000610 AC: 152AN: 249116Hom.: 2 AF XY: 0.000576 AC XY: 78AN XY: 135406
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GnomAD4 exome AF: 0.000217 AC: 317AN: 1460568Hom.: 2 Cov.: 36 AF XY: 0.000211 AC XY: 153AN XY: 726598
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GnomAD4 genome ? AF: 0.000375 AC: 57AN: 152186Hom.: 0 Cov.: 31 AF XY: 0.000443 AC XY: 33AN XY: 74424
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 27, 2018 | - - |
Focal segmental glomerulosclerosis 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 26, 2021 | - - |
Kidney disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 24, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
Cadd
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Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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