Genetic Variant ACTN3:p.Met27Arg (chr11-66547017-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001104.4(ACTN3):c.80T>G(p.Met27Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000774 in 1,524,666 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 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

ACTN3
NM_001104.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.49

Publications

0 publications found

Variant links:

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]

ACTN3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4 link	c.80T>G	p.Met27Arg	missense_variant	Exon 1 of 21	ENST00000513398.2	NP_001095.2	Q08043B4DZQ2
ACTN3	NM_001258371.3 link	c.276+231T>G		intron_variant	Intron 1 of 20		NP_001245300.2	Q08043A0A087WSZ2B4DZQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACTN3	ENST00000513398.2 link	c.80T>G	p.Met27Arg	missense_variant	Exon 1 of 21	1	NM_001104.4	ENSP00000426797.1	Q08043
ACTN3	ENST00000511191.1 link	n.80T>G		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000426236.1	D6RH00
ACTN3	ENST00000502692.5 link	c.276+231T>G		intron_variant	Intron 1 of 20	2		ENSP00000422007.1	A0A087WSZ2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000646

AC:

AN:

170248

AF XY:

0.0000774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000475

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000816

AC:

112

AN:

1372684

Hom.:

Cov.:

AF XY:

0.0000712

AC XY:

AN XY:

674394

show subpopulations

African (AFR)

AF:

0.0000330

AC:

AN:

30348

American (AMR)

AF:

0.0000337

AC:

AN:

29696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20074

East Asian (EAS)

AF:

0.00

AC:

AN:

38886

South Asian (SAS)

AF:

0.00

AC:

AN:

70634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4848

European-Non Finnish (NFE)

AF:

0.000102

AC:

109

AN:

1072478

Other (OTH)

AF:

0.0000178

AC:

AN:

56314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151982

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41366

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000503

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.80T>G (p.M27R) alteration is located in exon 1 (coding exon 1) of the ACTN3 gene. This alteration results from a T to G substitution at nucleotide position 80, causing the methionine (M) at amino acid position 27 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

MetaRNN

Pathogenic

0.83

PhyloP100

5.5

Sift4G

Uncertain

0.0050

Polyphen

0.68

Vest4

0.80

MVP

0.52

GERP RS

4.3

PromoterAI

0.0038

Neutral

(source)

Varity_R

0.85

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

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11-66547017-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over