14-68957305-C-T

Variant names:

• chr14-68957305-C-T
• rs2268973
• NM_001130004.2:c.105+21647G>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.105+21647G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,100 control chromosomes in the GnomAD database, including 5,269 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 0.26 (5269 hom., cov: 32)
• Consequence: ACTN1 NM_001130004.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.571
• Publications: 3 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=-0.7).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN1	NM_001130004.2	c.105+21647G>A		intron_variant	Intron 1 of 21	ENST00000394419.9	NP_001123476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN1	ENST00000394419.9	c.105+21647G>A		intron_variant	Intron 1 of 21	1	NM_001130004.2	ENSP00000377941.4

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39333 AN: 151982 Hom.: 5269 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.276

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

GnomAD4 genome AF: 0.259 AC: 39358 AN: 152100 Hom.: 5269 Cov.: 32 AF XY: 0.254 AC XY: 18915 AN XY: 74360

African (AFR) AF: 0.256 AC: 10615 AN: 41482

American (AMR) AF: 0.303 AC: 4629 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 654 AN: 3466

East Asian (EAS) AF: 0.108 AC: 561 AN: 5174

South Asian (SAS) AF: 0.205 AC: 990 AN: 4822

European-Finnish (FIN) AF: 0.223 AC: 2364 AN: 10592

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.275 AC: 18670 AN: 67982

Other (OTH) AF: 0.273 AC: 573 AN: 2102

Alfa AF: 0.274 Hom.: 9800

Bravo AF: 0.267

Asia WGS AF: 0.174 AC: 609 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.4
DANN	Benign	0.85
PhyloP100		-0.57
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)		0.0		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: rs2268973; hg19: chr14-69424022;