chr14-68919038-C-T

Variant names:

• chr14-68919038-C-T
• rs723113
• NM_001130004.2:c.340+1968G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001130004.2(ACTN1):​c.340+1968G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 152,126 control chromosomes in the GnomAD database, including 20,931 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 0.52 (20931 hom., cov: 33)
• Consequence: ACTN1 NM_001130004.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.400
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN1	NM_001130004.2	c.340+1968G>A		intron_variant	Intron 3 of 21	ENST00000394419.9	NP_001123476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN1	ENST00000394419.9	c.340+1968G>A		intron_variant	Intron 3 of 21	1	NM_001130004.2	ENSP00000377941.4

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78796 AN: 152008 Hom.: 20897 Cov.: 33

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.491

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

GnomAD4 genome AF: 0.519 AC: 78879 AN: 152126 Hom.: 20931 Cov.: 33 AF XY: 0.520 AC XY: 38655 AN XY: 74338

African (AFR) AF: 0.634 AC: 26315 AN: 41504

American (AMR) AF: 0.488 AC: 7467 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1593 AN: 3468

East Asian (EAS) AF: 0.311 AC: 1609 AN: 5172

South Asian (SAS) AF: 0.418 AC: 2018 AN: 4822

European-Finnish (FIN) AF: 0.543 AC: 5737 AN: 10564

Middle Eastern (MID) AF: 0.531 AC: 155 AN: 292

European-Non Finnish (NFE) AF: 0.479 AC: 32580 AN: 67980

Other (OTH) AF: 0.486 AC: 1026 AN: 2112

Alfa AF: 0.487 Hom.: 40461

Bravo AF: 0.519

Asia WGS AF: 0.359 AC: 1245 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.3
DANN	Benign	0.68
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs723113; hg19: chr14-69385755;