19-38647906-A-G

Variant names:

• chr19-38647906-A-G
• NM_004924.6:c.161A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_004924.6(ACTN4):​c.161A>G​(p.Lys54Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACTN4 NM_004924.6 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 5.74

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACTN4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 4.1552 (above the threshold of 3.09). Trascript score misZ: 5.6825 (above the threshold of 3.09). GenCC associations: The gene is linked to familial idiopathic steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis 1.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.161A>G	p.Lys54Arg	missense_variant, splice_region_variant	Exon 1 of 21	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.161A>G	p.Lys54Arg	missense_variant, splice_region_variant	Exon 1 of 21	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1218644 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 598252

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Corticosteroids response Other:1

May 20, 2022

Genetic Testing Lab, Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

Depending upon patients response to standard corticosteroids therapy, they were classified to be either Steroid resistance(SRNS)(poor metabolizer) or steroid sensitive(SSNS)(likley responsive) likley responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D;D;D
Sift4G	Benign	0.073	T;D;D
Polyphen		0.0010	B;.;.
Vest4		0.32
MutPred		0.71		Loss of methylation at K54 (P = 0.0071);Loss of methylation at K54 (P = 0.0071);Loss of methylation at K54 (P = 0.0071);
MVP		0.96
MPC		1.1
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.43
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39138546;