NM_004924.6:c.929G>A

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 (★★).

Frequency

Genomes: 𝑓 0.0097 ( 16 hom., cov: 33)
Exomes 𝑓: 0.015 ( 220 hom. )

Consequence

ACTN4
NM_004924.6 missense

Scores

3
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.57
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in the ACTN4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 4.1552 (above the threshold of 3.09). Trascript score misZ: 5.6825 (above the threshold of 3.09). GenCC associations: The gene is linked to familial idiopathic steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.00835824).
BP6
Variant 19-38717102-G-A is Benign according to our data. Variant chr19-38717102-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38717102-G-A is described in Lovd as [Benign]. Variant chr19-38717102-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00971 (1479/152350) while in subpopulation SAS AF= 0.0224 (108/4828). AF 95% confidence interval is 0.019. There are 16 homozygotes in gnomad4. There are 702 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1479 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTN4NM_004924.6 linkc.929G>A p.Arg310Gln missense_variant Exon 10 of 21 ENST00000252699.7 NP_004915.2 O43707-1A0A0S2Z3G9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTN4ENST00000252699.7 linkc.929G>A p.Arg310Gln missense_variant Exon 10 of 21 1 NM_004924.6 ENSP00000252699.2 O43707-1

Frequencies

GnomAD3 genomes
AF:
0.00972
AC:
1480
AN:
152232
Hom.:
16
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00268
Gnomad AMI
AF:
0.0329
Gnomad AMR
AF:
0.00857
Gnomad ASJ
AF:
0.00893
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0226
Gnomad FIN
AF:
0.00198
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.0151
Gnomad OTH
AF:
0.00766
GnomAD3 exomes
AF:
0.0118
AC:
2927
AN:
248854
Hom.:
33
AF XY:
0.0131
AC XY:
1762
AN XY:
134858
show subpopulations
Gnomad AFR exome
AF:
0.00213
Gnomad AMR exome
AF:
0.00534
Gnomad ASJ exome
AF:
0.0102
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0240
Gnomad FIN exome
AF:
0.00248
Gnomad NFE exome
AF:
0.0155
Gnomad OTH exome
AF:
0.0129
GnomAD4 exome
AF:
0.0146
AC:
21331
AN:
1461236
Hom.:
220
Cov.:
32
AF XY:
0.0151
AC XY:
10964
AN XY:
726904
show subpopulations
Gnomad4 AFR exome
AF:
0.00212
Gnomad4 AMR exome
AF:
0.00616
Gnomad4 ASJ exome
AF:
0.0115
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0241
Gnomad4 FIN exome
AF:
0.00297
Gnomad4 NFE exome
AF:
0.0158
Gnomad4 OTH exome
AF:
0.0126
GnomAD4 genome
AF:
0.00971
AC:
1479
AN:
152350
Hom.:
16
Cov.:
33
AF XY:
0.00942
AC XY:
702
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00267
Gnomad4 AMR
AF:
0.00856
Gnomad4 ASJ
AF:
0.00893
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0224
Gnomad4 FIN
AF:
0.00198
Gnomad4 NFE
AF:
0.0151
Gnomad4 OTH
AF:
0.00758
Alfa
AF:
0.0145
Hom.:
24
Bravo
AF:
0.00965
TwinsUK
AF:
0.0135
AC:
50
ALSPAC
AF:
0.0174
AC:
67
ESP6500AA
AF:
0.00272
AC:
12
ESP6500EA
AF:
0.0130
AC:
112
ExAC
AF:
0.0119
AC:
1446
Asia WGS
AF:
0.00866
AC:
31
AN:
3478
EpiCase
AF:
0.0154
EpiControl
AF:
0.0152

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 20, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 29, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16251236, 27535533, 21680739) -

not specified Benign:4
Jul 12, 2022
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis 1 Benign:2
Dec 05, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 07, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis Benign:1
Sep 06, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 14 Benign:1
-
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.31
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
T;.;T
Eigen
Benign
-0.083
Eigen_PC
Benign
0.073
FATHMM_MKL
Uncertain
0.90
D
MetaRNN
Benign
0.0084
T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.5
L;.;.
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-2.2
N;N;.
REVEL
Benign
0.080
Sift
Benign
0.13
T;T;.
Sift4G
Benign
0.28
T;T;T
Polyphen
0.0020
B;.;.
Vest4
0.17
MPC
1.5
ClinPred
0.014
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.21
gMVP
0.73

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: rs112545413; hg19: chr19-39207742; COSMIC: COSV99062847; API