chr14-68874876-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate

The NM_001130004.2(ACTN1):ā€‹c.2728G>Cā€‹(p.Gly910Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 7.0e-7 ( 0 hom. )

Consequence

ACTN1
NM_001130004.2 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.69
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN1. . Gene score misZ: 3.3621 (greater than the threshold 3.09). Trascript score misZ: 5.1933 (greater than threshold 3.09). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. GenCC has associacion of the gene with autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.91
PP5
Variant 14-68874876-C-G is Pathogenic according to our data. Variant chr14-68874876-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 988884.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACTN1NM_001130004.2 linkc.2728G>C p.Gly910Arg missense_variant 22/22 ENST00000394419.9 NP_001123476.1 P12814-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACTN1ENST00000394419.9 linkc.2728G>C p.Gly910Arg missense_variant 22/221 NM_001130004.2 ENSP00000377941.4 P12814-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.96e-7
AC:
1
AN:
1436594
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
709506
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.15e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Platelet-type bleeding disorder 15 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testing3billion, Medical GeneticsJan 03, 2022Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ACTN1 related disorder (PMID:27479822, PS1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.684, PP3_P). A missense variant is a common mechanism associated with Bleeding disorder (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1
Uncertain significance, no assertion criteria providedresearchBirmingham Platelet Group; University of BirminghamMay 01, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T;.;.;T;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D
MetaSVM
Uncertain
-0.026
T
MutationAssessor
Pathogenic
3.4
M;.;.;.;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.1
D;D;D;D;D
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
1.0
D;.;D;.;.
Vest4
0.94
MutPred
0.77
Gain of phosphorylation at S890 (P = 0.0905);.;.;.;.;
MVP
0.74
MPC
0.28
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.85
gMVP
0.79

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.

Other links and lift over

dbSNP: rs192640536; hg19: chr14-69341593; API