11-66551312-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001104.4(ACTN3):c.221G>A(p.Arg74His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,611,408 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00051 ( 0 hom. )
Consequence
ACTN3
NM_001104.4 missense
NM_001104.4 missense
Scores
6
4
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
ACTN3 (HGNC:165): (actinin alpha 3) This gene encodes a member of the alpha-actin binding protein gene family. The encoded protein is primarily expressed in skeletal muscle and functions as a structural component of sarcomeric Z line. This protein is involved in crosslinking actin containing thin filaments. An allelic polymorphism in this gene results in both coding and non-coding variants; the reference genome represents the coding allele. The non-functional allele of this gene is associated with elite athlete status. [provided by RefSeq, Feb 2014]
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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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.815
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN3 | NM_001104.4 | c.221G>A | p.Arg74His | missense_variant | 2/21 | ENST00000513398.2 | |
ACTN3 | NM_001258371.3 | c.350G>A | p.Arg117His | missense_variant | 2/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN3 | ENST00000513398.2 | c.221G>A | p.Arg74His | missense_variant | 2/21 | 1 | NM_001104.4 | P1 | |
ACTN3 | ENST00000502692.5 | c.350G>A | p.Arg117His | missense_variant | 2/21 | 2 | |||
ACTN3 | ENST00000511191.1 | c.*188G>A | 3_prime_UTR_variant, NMD_transcript_variant | 2/5 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000167 AC: 41AN: 245892Hom.: 0 AF XY: 0.000181 AC XY: 24AN XY: 132926
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GnomAD4 exome AF: 0.000510 AC: 744AN: 1459196Hom.: 0 Cov.: 31 AF XY: 0.000489 AC XY: 355AN XY: 725546
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GnomAD4 genome AF: 0.000237 AC: 36AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74356
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2021 | The c.221G>A (p.R74H) alteration is located in exon 2 (coding exon 2) of the ACTN3 gene. This alteration results from a G to A substitution at nucleotide position 221, causing the arginine (R) at amino acid position 74 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;D
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
MetaRNN
Pathogenic
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D
Polyphen
1.0
.;D
Vest4
MVP
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at