chr14-68925547-T-G

Variant names:

• chr14-68925547-T-G
• rs4899272
• NM_001130004.2:c.220+11A>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.220+11A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,606,296 control chromosomes in the GnomAD database, including 342,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.69 (36598 hom., cov: 29)
  • Exomes 𝑓: 0.64 (306198 hom.)
• Consequence: ACTN1 NM_001130004.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.136
• Publications: 14 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BP6: Variant 14-68925547-T-G is Benign according to our data. Variant chr14-68925547-T-G is described in ClinVar as Benign. ClinVar VariationId is 2414021.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN1	NM_001130004.2	MANE Select	c.220+11A>C		intron	N/A	NP_001123476.1	P12814-3
	ACTN1	NM_001424012.1		c.220+11A>C		intron	N/A	NP_001410941.1
	ACTN1	NM_001424013.1		c.220+11A>C		intron	N/A	NP_001410942.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN1	ENST00000394419.9	TSL:1 MANE Select	c.220+11A>C		intron	N/A	ENSP00000377941.4	P12814-3
	ACTN1	ENST00000538545.6	TSL:1	c.220+11A>C		intron	N/A	ENSP00000439828.2	P12814-4
	ACTN1	ENST00000193403.11	TSL:1	c.220+11A>C		intron	N/A	ENSP00000193403.6	P12814-1

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104240 AN: 151748 Hom.: 36548 Cov.: 29

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.990

Gnomad SAS AF: 0.879

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.663

GnomAD2 exomes AF: 0.713 AC: 175806 AN: 246644 AF XY: 0.710

Gnomad AFR exome AF: 0.756

Gnomad AMR exome AF: 0.823

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.990

Gnomad FIN exome AF: 0.709

Gnomad NFE exome AF: 0.604

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.641 AC: 932609 AN: 1454430 Hom.: 306198 Cov.: 29 AF XY: 0.647 AC XY: 467934 AN XY: 723460

African (AFR) AF: 0.759 AC: 25273 AN: 33314

American (AMR) AF: 0.810 AC: 35884 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14551 AN: 25830

East Asian (EAS) AF: 0.990 AC: 39144 AN: 39530

South Asian (SAS) AF: 0.861 AC: 73613 AN: 85544

European-Finnish (FIN) AF: 0.704 AC: 37462 AN: 53234

Middle Eastern (MID) AF: 0.622 AC: 3576 AN: 5750

European-Non Finnish (NFE) AF: 0.600 AC: 663724 AN: 1106814

Other (OTH) AF: 0.655 AC: 39382 AN: 60118

GnomAD4 genome AF: 0.687 AC: 104352 AN: 151866 Hom.: 36598 Cov.: 29 AF XY: 0.700 AC XY: 51918 AN XY: 74206

African (AFR) AF: 0.755 AC: 31256 AN: 41404

American (AMR) AF: 0.729 AC: 11124 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1965 AN: 3470

East Asian (EAS) AF: 0.990 AC: 5115 AN: 5166

South Asian (SAS) AF: 0.879 AC: 4217 AN: 4796

European-Finnish (FIN) AF: 0.709 AC: 7470 AN: 10538

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 41011 AN: 67916

Other (OTH) AF: 0.666 AC: 1405 AN: 2110

Alfa AF: 0.634 Hom.: 134080

Bravo AF: 0.688

Asia WGS AF: 0.914 AC: 3177 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.8
DANN	Benign	0.81
PhyloP100		-0.14
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: rs4899272; hg19: chr14-69392264; COSMIC: COSV51989703; COSMIC: COSV51989703;