rs112545413

Positions:

• chr19-38717102-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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:
  • Genomes: 𝑓 0.0097 (16 hom., cov: 33)
  • Exomes 𝑓: 0.015 (220 hom.)
• Consequence: ACTN4 NM_004924.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.57

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]

LOC107985291 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACTN4
• 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/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: 1480 AN: 152232 Hom.: 16 Cov.: 33

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

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

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

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:12

Revision: criteria provided, multiple submitters, no conflicts

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: 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;.;.
MutationTaster	Benign	1.0	D;D;D
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

Other links and lift over

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