19-38729366-C-G

Position:

• chr19-38729366-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.

• 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]

ACTN4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN4. . Gene score misZ 4.1552 (greater than the threshold 3.09). Trascript score misZ 5.6825 (greater than threshold 3.09). GenCC has associacion of gene with familial idiopathic steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31436324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.2670C>G	p.Asp890Glu	missense_variant	21/21	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.2670C>G	p.Asp890Glu	missense_variant	21/21	1	NM_004924.6	ENSP00000252699.2

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;.;.;.
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;