14-68884044-G-T

Variant names:

• chr14-68884044-G-T
• rs2273419
• NM_001130004.2:c.1635+124C>A

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.1635+124C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,046,124 control chromosomes in the GnomAD database, including 6,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1135 hom., cov: 32)
  • Exomes 𝑓: 0.10 (5199 hom.)
• Consequence: ACTN1 NM_001130004.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.66
• Publications: 6 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 14-68884044-G-T is Benign according to our data. Variant chr14-68884044-G-T is described in ClinVar as Benign. ClinVar VariationId is 1225619.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 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.1635+124C>A		intron	N/A	NP_001123476.1
	ACTN1	NM_001424012.1		c.1635+124C>A		intron	N/A	NP_001410941.1
	ACTN1	NM_001424013.1		c.1761+124C>A		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.1635+124C>A		intron	N/A	ENSP00000377941.4
	ACTN1	ENST00000538545.6	TSL:1	c.1635+124C>A		intron	N/A	ENSP00000439828.2
	ACTN1	ENST00000193403.11	TSL:1	c.1635+124C>A		intron	N/A	ENSP00000193403.6

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17794 AN: 152028 Hom.: 1129 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0538

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.104 AC: 93367 AN: 893978 Hom.: 5199 AF XY: 0.105 AC XY: 46279 AN XY: 441772

African (AFR) AF: 0.163 AC: 3329 AN: 20438

American (AMR) AF: 0.0663 AC: 1194 AN: 18018

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 1681 AN: 15556

East Asian (EAS) AF: 0.0719 AC: 2292 AN: 31886

South Asian (SAS) AF: 0.116 AC: 5306 AN: 45782

European-Finnish (FIN) AF: 0.140 AC: 5673 AN: 40480

Middle Eastern (MID) AF: 0.0917 AC: 282 AN: 3074

European-Non Finnish (NFE) AF: 0.102 AC: 69365 AN: 679196

Other (OTH) AF: 0.107 AC: 4245 AN: 39548

GnomAD4 genome AF: 0.117 AC: 17825 AN: 152146 Hom.: 1135 Cov.: 32 AF XY: 0.118 AC XY: 8790 AN XY: 74398

African (AFR) AF: 0.161 AC: 6693 AN: 41478

American (AMR) AF: 0.0756 AC: 1157 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3470

East Asian (EAS) AF: 0.0535 AC: 277 AN: 5176

South Asian (SAS) AF: 0.124 AC: 600 AN: 4824

European-Finnish (FIN) AF: 0.144 AC: 1529 AN: 10586

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6873 AN: 67994

Other (OTH) AF: 0.116 AC: 246 AN: 2114

Alfa AF: 0.103 Hom.: 1986

Bravo AF: 0.113

Asia WGS AF: 0.0800 AC: 280 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

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	-0.88
CADD	Benign	0.81
DANN	Benign	0.63
PhyloP100		-1.7
PromoterAI		-0.026	Neutral
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: rs2273419; hg19: chr14-69350761;