chr19-38647770-C-G

Variant names:

• chr19-38647770-C-G
• rs764029233
• NM_004924.6:c.25C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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. 13/22 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18685687).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004924.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.25C>G	p.Gln9Glu	missense	Exon 1 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.25C>G	p.Gln9Glu	missense	Exon 1 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.25C>G	p.Gln9Glu	missense	Exon 1 of 22	NP_001427229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.25C>G	p.Gln9Glu	missense	Exon 1 of 21	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.25C>G	p.Gln9Glu	missense	Exon 1 of 21	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.25C>G	p.Gln9Glu	missense	Exon 1 of 14	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000127 AC: 2 AN: 157510 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 30002

American (AMR) AF: 0.00 AC: 0 AN: 36816

Ashkenazi Jewish (ASJ) AF: 0.000242 AC: 6 AN: 24806

East Asian (EAS) AF: 0.00 AC: 0 AN: 34154

South Asian (SAS) AF: 0.00 AC: 0 AN: 79298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083278

Other (OTH) AF: 0.0000172 AC: 1 AN: 57996

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000864 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.41
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.11
Sift	Benign	0.048	D
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.13		Loss of helix (P = 0.0558)
MVP		0.63
MPC		1.4
ClinPred		0.089	T
GERP RS		4.8
PromoterAI		0.059	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.26
gMVP		0.59
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs764029233; hg19: chr19-39138410;