NM_001130004.2:c.515+193T>C

Variant names:

• chr14-68909762-A-G
• rs743127
• NM_001130004.2:c.515+193T>C

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.515+193T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 152,060 control chromosomes in the GnomAD database, including 28,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.60 (28059 hom., cov: 32)
• Consequence: ACTN1 NM_001130004.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0190
• Publications: 4 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=-0.93).
• BP6: Variant 14-68909762-A-G is Benign according to our data. Variant chr14-68909762-A-G is described in ClinVar as Benign. ClinVar VariationId is 1294078.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 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.515+193T>C		intron	N/A	NP_001123476.1
	ACTN1	NM_001424012.1		c.515+193T>C		intron	N/A	NP_001410941.1
	ACTN1	NM_001424013.1		c.641+193T>C		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.515+193T>C		intron	N/A	ENSP00000377941.4
	ACTN1	ENST00000538545.6	TSL:1	c.515+193T>C		intron	N/A	ENSP00000439828.2
	ACTN1	ENST00000193403.11	TSL:1	c.515+193T>C		intron	N/A	ENSP00000193403.6

Frequencies

GnomAD3 genomes AF: 0.599 AC: 91088 AN: 151942 Hom.: 28024 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.935

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.574

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

GnomAD4 genome AF: 0.600 AC: 91178 AN: 152060 Hom.: 28059 Cov.: 32 AF XY: 0.612 AC XY: 45509 AN XY: 74342

African (AFR) AF: 0.678 AC: 28126 AN: 41472

American (AMR) AF: 0.554 AC: 8470 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1847 AN: 3466

East Asian (EAS) AF: 0.935 AC: 4822 AN: 5158

South Asian (SAS) AF: 0.794 AC: 3832 AN: 4824

European-Finnish (FIN) AF: 0.647 AC: 6850 AN: 10592

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35312 AN: 67956

Other (OTH) AF: 0.579 AC: 1222 AN: 2112

Alfa AF: 0.523 Hom.: 38326

Bravo AF: 0.588

Asia WGS AF: 0.843 AC: 2927 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.3
DANN	Benign	0.29
PhyloP100		0.019
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs743127; hg19: chr14-69376479;