chr14-68874936-T-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 3P and 14B. PM1PP2BP4_StrongBP6_ModerateBS1BS2

The NM_001130004.2(ACTN1):c.2668A>T(p.Thr890Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,612,820 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 33)

Exomes 𝑓: 0.014 ( 186 hom. )

Consequence

ACTN1
NM_001130004.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0900

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity ACTN1_HUMAN

PP2

Missense variant in the ACTN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 3.3621 (above the threshold of 3.09). Trascript score misZ: 5.1933 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036654174).

BP6

Variant 14-68874936-T-A is Benign according to our data. Variant chr14-68874936-T-A is described in ClinVar as [Benign]. Clinvar id is 2014611.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0113 (1715/152214) while in subpopulation AMR AF= 0.0188 (288/15294). AF 95% confidence interval is 0.017. There are 19 homozygotes in gnomad4. There are 799 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1715 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN1	NM_001130004.2 link	c.2668A>T	p.Thr890Ser	missense_variant	Exon 22 of 22	ENST00000394419.9	NP_001123476.1	P12814-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN1	ENST00000394419.9 link	c.2668A>T	p.Thr890Ser	missense_variant	Exon 22 of 22	1	NM_001130004.2	ENSP00000377941.4		P12814-3

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1715

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0111

AC:

2778

AN:

249814

Hom.:

AF XY:

0.0111

AC XY:

1500

AN XY:

135324

show subpopulations

Gnomad AFR exome

AF:

0.00255

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0217

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.00145

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0185

GnomAD4 exome

AF:

0.0140

AC:

20479

AN:

1460606

Hom.:

186

Cov.:

AF XY:

0.0138

AC XY:

10014

AN XY:

726444

show subpopulations

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.0151

Gnomad4 ASJ exome

AF:

0.0202

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00288

Gnomad4 FIN exome

AF:

0.00170

Gnomad4 NFE exome

AF:

0.0161

Gnomad4 OTH exome

AF:

0.0137

GnomAD4 genome

AF:

0.0113

AC:

1715

AN:

152214

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

799

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.0188

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.000943

Gnomad4 NFE

AF:

0.0157

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0159

Hom.:

Bravo

AF:

0.0132

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0165

AC:

142

ExAC

AF:

0.0105

AC:

1279

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0196

EpiControl

AF:

0.0215

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.4

DANN

Benign

0.85

DEOGEN2

Benign

0.11

T;.;.;T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.52

T;T;T;T;T

MetaRNN

Benign

0.0037

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.035

N;.;.;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

0.28

N;N;N;N;N

REVEL

Benign

0.070

Sift

Benign

0.69

T;T;T;T;T

Sift4G

Benign

0.91

T;T;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.037

MutPred

0.39

Gain of catalytic residue at Y867 (P = 0);.;.;.;.;

MPC

0.033

ClinPred

0.00053

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.25

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over