14-68874876-C-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_001130004.2(ACTN1):āc.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
NM_001130004.2 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.69
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]
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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
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.96e-7 AC: 1AN: 1436594Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 709506
GnomAD4 exome
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1
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1436594
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31
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0
AN XY:
709506
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GnomAD4 genome Cov.: 33
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 submitter | clinical testing | 3billion, Medical Genetics | Jan 03, 2022 | Same 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 provided | research | Birmingham Platelet Group; University of Birmingham | May 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;.;D;.;.
Vest4
MutPred
Gain of phosphorylation at S890 (P = 0.0905);.;.;.;.;
MVP
MPC
0.28
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at