19-38647770-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_004924.6(ACTN4):c.25C>G(p.Gln9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000571 in 1,400,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: ACTN4 NM_004924.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.406

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a region_of_interest Actin-binding (size 268) in uniprot entity ACTN4_HUMAN there are 16 pathogenic changes around while only 4 benign (80%) in NM_004924.6
• PP2: Missense variant where missense usually causes diseases, ACTN4
• BP4: Computational evidence support a benign effect (MetaRNN=0.18685687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.25C>G	p.Gln9Glu	missense_variant	1/21	ENST00000252699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.25C>G	p.Gln9Glu	missense_variant	1/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000127 AC: 2 AN: 157510 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 85836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000571 AC: 8 AN: 1400428 Hom.: 0 Cov.: 31 AF XY: 0.00000578 AC XY: 4 AN XY: 692596

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000242

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000864 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 26, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals with ACTN4-related conditions. This variant is present in population databases (rs764029233, ExAC 0.01%). This sequence change replaces glutamine with glutamic acid at codon 9 of the ACTN4 protein (p.Gln9Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.70	N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.29	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.048	D;D;D
Sift4G	Benign	0.34	T;D;D
Polyphen		0.0	B;.;.
Vest4		0.17
MutPred		0.13		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.63
MPC		1.4
ClinPred		0.089	T
GERP RS		4.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.26
gMVP		0.59

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: rs764029233; hg19: chr19-39138410;