rs371440985

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001130004.2(ACTN1):​c.2612G>T​(p.Arg871Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

ACTN1
NM_001130004.2 missense

Scores

1
11
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.11
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTN1NM_001130004.2 linkc.2612G>T p.Arg871Leu 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
ACTN1ENST00000394419.9 linkc.2612G>T p.Arg871Leu missense_variant Exon 22 of 22 1 NM_001130004.2 ENSP00000377941.4 P12814-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.010
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.45
T;.;.;T;.
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Benign
0.041
D
MetaRNN
Uncertain
0.56
D;D;D;D;D
MetaSVM
Benign
-0.47
T
MutationAssessor
Uncertain
2.2
M;.;.;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-5.4
D;D;D;D;D
REVEL
Uncertain
0.35
Sift
Uncertain
0.0050
D;D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D;D
Polyphen
0.016
B;.;B;.;.
Vest4
0.54
MutPred
0.75
Gain of catalytic residue at P853 (P = 0.001);.;.;.;.;
MVP
0.48
MPC
0.052
ClinPred
0.98
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.65
gMVP
0.77

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: rs371440985; hg19: chr14-69341709; API