Genetic Variant ACTN4:c.162+6C>T (chr19-38647913-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_004924.6(ACTN4):c.162+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000653 in 1,392,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

ACTN4
NM_004924.6 splice_region, intron

Scores

Splicing: ADA: 0.05421

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0440

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.21).

BP6

Variant 19-38647913-C-T is Benign according to our data. Variant chr19-38647913-C-T is described in ClinVar as Benign. ClinVar VariationId is 2170282.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000137 (20/146000) while in subpopulation EAS AF = 0.00425 (20/4706). AF 95% confidence interval is 0.00282. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 20 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ACTN4	NM_004924.6	MANE Select	c.162+6C>T	splice_region intron	N/A	NP_004915.2
ACTN4	NM_001440296.1		c.162+6C>T	splice_region intron	N/A	NP_001427225.1
ACTN4	NM_001440300.1		c.162+6C>T	splice_region intron	N/A	NP_001427229.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.162+6C>T	splice_region intron	N/A	ENSP00000252699.2	O43707-1
ACTN4	ENST00000424234.7	TSL:1	c.162+6C>T	splice_region intron	N/A	ENSP00000411187.4	F5GXS2
ACTN4	ENST00000390009.7	TSL:1	c.162+6C>T	splice_region intron	N/A	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes

AF:

0.000137

AC:

AN:

145878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000229

AC:

AN:

100546

AF XY:

0.000180

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000487

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1246982

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

611610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23972

American (AMR)

AF:

0.00

AC:

AN:

23952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18610

East Asian (EAS)

AF:

0.00121

AC:

AN:

26382

South Asian (SAS)

AF:

0.00

AC:

AN:

67222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3662

European-Non Finnish (NFE)

AF:

0.0000332

AC:

AN:

995110

Other (OTH)

AF:

0.000124

AC:

AN:

48544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000137

AC:

AN:

146000

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

71054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38964

American (AMR)

AF:

0.00

AC:

AN:

14526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00425

AC:

AN:

4706

South Asian (SAS)

AF:

0.00

AC:

AN:

4372

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66938

Other (OTH)

AF:

0.00

AC:

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000110

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.044

PromoterAI

0.049

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.054

dbscSNV1_RF

Benign

0.21

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over