Genetic Variant ACTN3:p.Glu14Val (chr11-66546978-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001104.4(ACTN3):c.41A>T(p.Glu14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,370,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign 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. E14A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

ACTN3
NM_001104.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.614

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19960225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4 link	c.41A>T	p.Glu14Val	missense_variant	Exon 1 of 21	ENST00000513398.2	NP_001095.2	Q08043B4DZQ2
ACTN3	NM_001258371.3 link	c.276+192A>T		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.41A>T	p.Glu14Val	missense_variant	Exon 1 of 21	1	NM_001104.4	ENSP00000426797.1	Q08043
ACTN3	ENST00000511191.1 link	n.41A>T		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000426236.1	D6RH00
ACTN3	ENST00000502692.5 link	c.276+192A>T		intron_variant	Intron 1 of 20	2		ENSP00000422007.1	A0A087WSZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.29e-7

AC:

AN:

1370874

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

673230

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30402

American (AMR)

AF:

0.00

AC:

AN:

29434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20342

East Asian (EAS)

AF:

0.00

AC:

AN:

38558

South Asian (SAS)

AF:

0.00

AC:

AN:

70776

European-Finnish (FIN)

AF:

0.0000205

AC:

AN:

48708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071090

Other (OTH)

AF:

0.00

AC:

AN:

56314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

0.17

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.22

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.49

MetaRNN

Benign

0.20

PhyloP100

0.61

Sift4G

Benign

0.19

Polyphen

0.0

Vest4

0.40

MVP

0.60

GERP RS

0.45

PromoterAI

0.0048

Neutral

(source)

Varity_R

0.079

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over