rs141727248

chr19-38728009-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004924.6(ACTN4):c.2401G>A(p.Val801Met) variant causes a missense change. The variant allele was found at a frequency of 0.00579 in 1,612,964 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0060 (27 hom.)
• Consequence: ACTN4 NM_004924.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.66

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACTN4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011119425).
• BP6: Variant 19-38728009-G-A is Benign according to our data. Variant chr19-38728009-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38728009-G-A is described in Lovd as [Benign]. Variant chr19-38728009-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00383 (583/152150) while in subpopulation NFE AF= 0.00634 (431/67960). AF 95% confidence interval is 0.00585. There are 2 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 583 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.2401G>A	p.Val801Met	missense_variant	19/21	ENST00000252699.7
LOC107985291	XR_001753937.2	n.169+179C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.2401G>A	p.Val801Met	missense_variant	19/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 583 AN: 152032 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00634

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00365 AC: 906 AN: 248452 Hom.: 1 AF XY: 0.00384 AC XY: 518 AN XY: 134950

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00504

Gnomad NFE exome AF: 0.00605

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00600 AC: 8763 AN: 1460814 Hom.: 27 Cov.: 32 AF XY: 0.00583 AC XY: 4237 AN XY: 726686

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00637

Gnomad4 NFE exome AF: 0.00716

Gnomad4 OTH exome AF: 0.00484

GnomAD4 genome AF: 0.00383 AC: 583 AN: 152150 Hom.: 2 Cov.: 31 AF XY: 0.00350 AC XY: 260 AN XY: 74382

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00634

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00549 Hom.: 5

Bravo AF: 0.00351

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00358 AC: 434

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00570

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2019	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	ACTN4: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Focal segmental glomerulosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 11, 2022

- -

Focal segmental glomerulosclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.90	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.064	T;T;T
Polyphen		0.013	B;.;.
Vest4		0.64
MVP		0.67
MPC		0.84
ClinPred		0.011	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.94

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: rs141727248; hg19: chr19-39218649; COSMIC: COSV99062848; COSMIC: COSV99062848;