rs141727248

Variant names:

• chr19-38728009-G-A
• rs141727248
• NM_004924.6:c.2401G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38728009-G-A
• chr19-38728009-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• 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:12
• Conservation: PhyloP100: 3.66
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 259574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 583 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.2401G>A	p.Val801Met	missense	Exon 19 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.2401G>A	p.Val801Met	missense	Exon 19 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.2401G>A	p.Val801Met	missense	Exon 19 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.2401G>A	p.Val801Met	missense	Exon 19 of 21	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.2401G>A	p.Val801Met	missense	Exon 19 of 21	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.1744G>A	p.Val582Met	missense	Exon 12 of 14	ENSP00000439497.1	O43707-2

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

GnomAD2 exomes AF: 0.00365 AC: 906 AN: 248452 AF XY: 0.00384

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 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

African (AFR) AF: 0.000807 AC: 27 AN: 33478

American (AMR) AF: 0.00235 AC: 105 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86182

European-Finnish (FIN) AF: 0.00637 AC: 335 AN: 52624

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

European-Non Finnish (NFE) AF: 0.00716 AC: 7964 AN: 1111886

Other (OTH) AF: 0.00484 AC: 292 AN: 60368

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

African (AFR) AF: 0.00123 AC: 51 AN: 41530

American (AMR) AF: 0.00235 AC: 36 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00634 AC: 431 AN: 67960

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00519 Hom.: 7

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Focal segmental glomerulosclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.15
Sift	Benign	0.11	T
Sift4G	Benign	0.064	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
Mutation Taster		=89/11	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: rs141727248; hg19: chr19-39218649; COSMIC: COSV99062848; COSMIC: COSV99062848;