dbSNP rs1475034: ACTN1:c.*816C>A (chr14-68874043-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001130004.2(ACTN1):c.*816C>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 152,110 control chromosomes in the GnomAD database, including 4,484 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 4482 hom., cov: 32)

Exomes 𝑓: 0.23 ( 2 hom. )

Consequence

ACTN1
NM_001130004.2 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.630

Publications

6 publications found

Variant links:

Genes affected

ACTN1 (HGNC:163): (actinin alpha 1) 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, cytoskeletal, alpha actinin isoform and maps to the same site as the structurally similar erythroid beta spectrin gene. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACTN1 Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 15
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTN1 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=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130004.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACTN1	NM_001130004.2	MANE Select	c.*816C>A	downstream_gene	N/A	NP_001123476.1	P12814-3
ACTN1	NM_001424012.1		c.*816C>A	downstream_gene	N/A	NP_001410941.1
ACTN1	NM_001424013.1		c.*816C>A	downstream_gene	N/A	NP_001410942.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACTN1	ENST00000394419.9	TSL:1 MANE Select	c.*816C>A	downstream_gene	N/A	ENSP00000377941.4	P12814-3
ACTN1	ENST00000193403.11	TSL:1	c.*816C>A	downstream_gene	N/A	ENSP00000193403.6	P12814-1
ACTN1	ENST00000904825.1		c.*816C>A	downstream_gene	N/A	ENSP00000574884.1

Frequencies

GnomAD3 genomes

AF:

0.238

AC:

36193

AN:

151838

Hom.:

4479

Cov.:

show subpopulations

Gnomad AFR

AF:

0.266

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.165

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.0649

Gnomad SAS

AF:

0.166

Gnomad FIN

AF:

0.282

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.251

Gnomad OTH

AF:

0.234

GnomAD4 exome

AF:

0.234

AC:

AN:

154

Hom.:

AF XY:

0.239

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.221

AC:

AN:

136

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.400

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.238

AC:

36216

AN:

151956

Hom.:

4482

Cov.:

AF XY:

0.235

AC XY:

17469

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.266

AC:

11019

AN:

41430

American (AMR)

AF:

0.165

AC:

2513

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

766

AN:

3470

East Asian (EAS)

AF:

0.0648

AC:

335

AN:

5166

South Asian (SAS)

AF:

0.167

AC:

804

AN:

4810

European-Finnish (FIN)

AF:

0.282

AC:

2973

AN:

10536

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.251

AC:

17081

AN:

67966

Other (OTH)

AF:

0.231

AC:

488

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1383

2766

4148

5531

6914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.244

Hom.:

9357

Bravo

AF:

0.229

Asia WGS

AF:

0.106

AC:

371

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.8

(source)

DANN

Benign

0.71

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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