rs34491236

chr19-38710261-C-Gchr19-38710261-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PP2 PP3 BS1_Supporting

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 (★). Synonymous variant affecting the same amino acid position (i.e. I246I) has been classified as Benign.

• 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

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]

LOC107985291 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Calponin-homology (CH) 2 (size 106) in uniprot entity ACTN4_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_004924.6
• PP2: Missense variant where missense usually causes diseases, ACTN4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome 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 gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.738C>G	p.Ile246Met	missense_variant	8/21	ENST00000252699.7
LOC107985291	XR_001753937.2	n.170-8097G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.738C>G	p.Ile246Met	missense_variant	8/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251310 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135840

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 SAS exome AF: 0.0000980

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 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

GeneDx

Jan 10, 2017

The I246M variant in the ACTN4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I246M variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I246M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I246M as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D;D
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

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: rs34491236; hg19: chr19-39200901;