19-38704918-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004924.6(ACTN4):c.398-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,611,324 control chromosomes in the GnomAD database, including 3,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 251 hom., cov: 33)

Exomes 𝑓: 0.065 ( 3445 hom. )

Consequence

ACTN4
NM_004924.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.466

Publications

10 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTN4 links:

ENSG00000298338 (HGNC:):

ENSG00000298338 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 19-38704918-C-T is Benign according to our data. Variant chr19-38704918-C-T is described in ClinVar as Benign. ClinVar VariationId is 259579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.398-16C>T		intron_variant	Intron 3 of 20	ENST00000252699.7	NP_004915.2	O43707-1A0A0S2Z3G9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7 link	c.398-16C>T		intron_variant	Intron 3 of 20	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.0558

AC:

8485

AN:

152186

Hom.:

252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0484

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0578

Gnomad ASJ

AF:

0.0565

Gnomad EAS

AF:

0.0460

Gnomad SAS

AF:

0.0965

Gnomad FIN

AF:

0.0219

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0633

Gnomad OTH

AF:

0.0583

GnomAD2 exomes

AF:

0.0623

AC:

15652

AN:

251436

AF XY:

0.0639

show subpopulations

Gnomad AFR exome

AF:

0.0493

Gnomad AMR exome

AF:

0.0678

Gnomad ASJ exome

AF:

0.0604

Gnomad EAS exome

AF:

0.0397

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.0621

Gnomad OTH exome

AF:

0.0662

GnomAD4 exome

AF:

0.0653

AC:

95220

AN:

1459020

Hom.:

3445

Cov.:

AF XY:

0.0662

AC XY:

48087

AN XY:

726130

show subpopulations

African (AFR)

AF:

0.0499

AC:

1667

AN:

33424

American (AMR)

AF:

0.0709

AC:

3170

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0622

AC:

1624

AN:

26126

East Asian (EAS)

AF:

0.0453

AC:

1799

AN:

39690

South Asian (SAS)

AF:

0.102

AC:

8750

AN:

86198

European-Finnish (FIN)

AF:

0.0251

AC:

1338

AN:

53410

Middle Eastern (MID)

AF:

0.0686

AC:

395

AN:

5760

European-Non Finnish (NFE)

AF:

0.0654

AC:

72548

AN:

1109396

Other (OTH)

AF:

0.0652

AC:

3929

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

4658

9317

13975

18634

23292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2790

5580

8370

11160

13950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0557

AC:

8489

AN:

152304

Hom.:

251

Cov.:

AF XY:

0.0548

AC XY:

4084

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0484

AC:

2013

AN:

41550

American (AMR)

AF:

0.0577

AC:

883

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0565

AC:

196

AN:

3472

East Asian (EAS)

AF:

0.0461

AC:

239

AN:

5184

South Asian (SAS)

AF:

0.0960

AC:

463

AN:

4824

European-Finnish (FIN)

AF:

0.0219

AC:

233

AN:

10620

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0633

AC:

4309

AN:

68022

Other (OTH)

AF:

0.0591

AC:

125

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

409

818

1227

1636

2045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0631

Hom.:

392

Bravo

AF:

0.0584

Asia WGS

AF:

0.0890

AC:

308

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.9

(source)

DANN

Benign

0.74

PhyloP100

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over