chr14-68873882-C-T

Variant names:

• chr14-68873882-C-T
• rs181456
• NM_001130004.2:c.*977G>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.*977G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 151,918 control chromosomes in the GnomAD database, including 10,130 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 0.36 (10130 hom., cov: 33)
• Consequence: ACTN1 NM_001130004.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.316
• 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=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN1	NM_001130004.2	c.*977G>A		downstream_gene_variant		ENST00000394419.9	NP_001123476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN1	ENST00000394419.9	c.*977G>A		downstream_gene_variant		1	NM_001130004.2	ENSP00000377941.4

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54791 AN: 151800 Hom.: 10123 Cov.: 33

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.352

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

GnomAD4 genome AF: 0.361 AC: 54833 AN: 151918 Hom.: 10130 Cov.: 33 AF XY: 0.356 AC XY: 26435 AN XY: 74238

African (AFR) AF: 0.347 AC: 14389 AN: 41418

American (AMR) AF: 0.295 AC: 4499 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1261 AN: 3466

East Asian (EAS) AF: 0.199 AC: 1027 AN: 5172

South Asian (SAS) AF: 0.359 AC: 1732 AN: 4822

European-Finnish (FIN) AF: 0.380 AC: 3999 AN: 10516

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26706 AN: 67958

Other (OTH) AF: 0.356 AC: 748 AN: 2102

Alfa AF: 0.260 Hom.: 656

Bravo AF: 0.348

Asia WGS AF: 0.340 AC: 1183 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.4
DANN	Benign	0.85
PhyloP100		-0.32

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs181456; hg19: chr14-69340599;