dbSNP rs747126112: ACTN3:p.Met27Thr (chr11-66547017-T-C) – 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>C(p.Met27Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,372,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M27R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ACTN3
NM_001104.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4 link	c.80T>C	p.Met27Thr	missense_variant	Exon 1 of 21	ENST00000513398.2	NP_001095.2	Q08043B4DZQ2
ACTN3	NM_001258371.3 link	c.276+231T>C		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>C	p.Met27Thr	missense_variant	Exon 1 of 21	1	NM_001104.4	ENSP00000426797.1	Q08043
ACTN3	ENST00000511191.1 link	n.80T>C		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000426236.1	D6RH00
ACTN3	ENST00000502692.5 link	c.276+231T>C		intron_variant	Intron 1 of 20	2		ENSP00000422007.1	A0A087WSZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000587

AC:

AN:

170248

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1372684

Hom.:

Cov.:

AF XY:

0.00000445

AC XY:

AN XY:

674394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30348

American (AMR)

AF:

0.00

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:

0.00000466

AC:

AN:

1072478

Other (OTH)

AF:

0.00

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.35

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

MetaRNN

Pathogenic

0.82

PhyloP100

5.5

Sift4G

Benign

0.14

Polyphen

0.46

Vest4

0.77

MVP

0.52

GERP RS

4.3

PromoterAI

0.045

Neutral

(source)

Varity_R

0.52

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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rs747126112

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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