19-38710261-C-G

Variant names:

• chr19-38710261-C-G
• rs34491236
• NM_004924.6:c.738C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP3 BS1_Supporting BS2

The NM_004924.6(ACTN4):​c.738C>G​(p.Ile246Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I246L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ACTN4 NM_004924.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.659
• Publications: 2 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

ENSG00000298338 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004924.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000821 (12/1461774) while in subpopulation SAS AF = 0.000139 (12/86250). AF 95% confidence interval is 0.00008. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 12 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.738C>G	p.Ile246Met	missense	Exon 8 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.738C>G	p.Ile246Met	missense	Exon 8 of 22	NP_001427225.1
	ACTN4	NM_001440298.1		c.738C>G	p.Ile246Met	missense	Exon 8 of 21	NP_001427227.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.738C>G	p.Ile246Met	missense	Exon 8 of 21	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.733+785C>G		intron	N/A	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.163-4208C>G		intron	N/A	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251310 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.00000821 AC: 12 AN: 1461774 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	-0.89	N
PhyloP100		0.66
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.58
Sift	Benign	0.59	T
Sift4G	Benign	0.83	T
Polyphen		0.0060	B
Vest4		0.86
MutPred		0.71		Gain of disorder (P = 0.056)
MVP		0.97
MPC		2.6
ClinPred		0.18	T
GERP RS		4.4
Varity_R		0.33
gMVP		0.87
Mutation Taster		=36/64	disease causing

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: rs34491236; hg19: chr19-39200901;