rs112545413
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_004924.6(ACTN4):c.929G>A(p.Arg310Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,586 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R310W) has been classified as Uncertain significance.
Frequency
Consequence
NM_004924.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN4 | NM_004924.6 | c.929G>A | p.Arg310Gln | missense_variant | 10/21 | ENST00000252699.7 | |
LOC107985291 | XR_001753937.2 | n.169+11086C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN4 | ENST00000252699.7 | c.929G>A | p.Arg310Gln | missense_variant | 10/21 | 1 | NM_004924.6 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00972 AC: 1480AN: 152232Hom.: 16 Cov.: 33
GnomAD3 exomes AF: 0.0118 AC: 2927AN: 248854Hom.: 33 AF XY: 0.0131 AC XY: 1762AN XY: 134858
GnomAD4 exome AF: 0.0146 AC: 21331AN: 1461236Hom.: 220 Cov.: 32 AF XY: 0.0151 AC XY: 10964AN XY: 726904
GnomAD4 genome ? AF: 0.00971 AC: 1479AN: 152350Hom.: 16 Cov.: 33 AF XY: 0.00942 AC XY: 702AN XY: 74502
ClinVar
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 12, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2020 | This variant is associated with the following publications: (PMID: 16251236, 27535533, 21680739) - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 20, 2018 | - - |
Focal segmental glomerulosclerosis 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Focal segmental glomerulosclerosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Sep 06, 2022 | - - |
Intellectual disability, autosomal dominant 14 Benign:1
Likely benign, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The p.Arg310Gln variant in ACTN4 has been identified in at least 2 individuals with focal and segmental glomerulosclerosis, but did not segregate with disease and was also present in at least 4 unaffected individuals (PMID: 16251236). This variant has also been identified in >2% of South Asian chromosomes and 15 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg310Gln variant may impact protein function (PMID: 21680739). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant focal and segmental glomerulosclerosis. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at