rs12050161

Variant names:

• chr14-68893914-T-C
• rs12050161
• NM_001130004.2:c.763-167A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001130004.2(ACTN1):​c.763-167A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 151,870 control chromosomes in the GnomAD database, including 2,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (2853 hom., cov: 31)
• Consequence: ACTN1 NM_001130004.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.267
• Publications: 10 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-68893914-T-C is Benign according to our data. Variant chr14-68893914-T-C is described in ClinVar as Benign. ClinVar VariationId is 1231211.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.247 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN1	NM_001130004.2	MANE Select	c.763-167A>G		intron	N/A	NP_001123476.1
	ACTN1	NM_001424012.1		c.763-167A>G		intron	N/A	NP_001410941.1
	ACTN1	NM_001424013.1		c.889-167A>G		intron	N/A	NP_001410942.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN1	ENST00000394419.9	TSL:1 MANE Select	c.763-167A>G		intron	N/A	ENSP00000377941.4
	ACTN1	ENST00000538545.6	TSL:1	c.763-167A>G		intron	N/A	ENSP00000439828.2
	ACTN1	ENST00000193403.11	TSL:1	c.763-167A>G		intron	N/A	ENSP00000193403.6

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28530 AN: 151752 Hom.: 2853 Cov.: 31

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.188 AC: 28557 AN: 151870 Hom.: 2853 Cov.: 31 AF XY: 0.191 AC XY: 14155 AN XY: 74232

African (AFR) AF: 0.239 AC: 9898 AN: 41358

American (AMR) AF: 0.217 AC: 3319 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 859 AN: 3468

East Asian (EAS) AF: 0.198 AC: 1020 AN: 5146

South Asian (SAS) AF: 0.259 AC: 1244 AN: 4800

European-Finnish (FIN) AF: 0.107 AC: 1125 AN: 10562

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10448 AN: 67954

Other (OTH) AF: 0.204 AC: 432 AN: 2114

Alfa AF: 0.168 Hom.: 8580

Bravo AF: 0.196

Asia WGS AF: 0.231 AC: 802 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.8
DANN	Benign	0.80
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12050161; hg19: chr14-69360631;