19-38729366-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004924.6(ACTN4):c.2670C>G(p.Asp890Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. D890D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTN4 NM_004924.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ACTN4
• BP4: Computational evidence support a benign effect (MetaRNN=0.31436324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.2670C>G	p.Asp890Glu	missense_variant	21/21	ENST00000252699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.2670C>G	p.Asp890Glu	missense_variant	21/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.084
Dann	Benign	0.45
DEOGEN2	Benign	0.40	T;.;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.28	N
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.49
MutPred		0.42		Loss of relative solvent accessibility (P = 0.107);.;.;.;
MVP		0.69
MPC		1.7
ClinPred		0.69	D
GERP RS		-7.0
Varity_R		0.12
gMVP		0.43

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: rs113969422; hg19: chr19-39220006;