Variant 11-66547043-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001104.4(ACTN3):c.106G>C(p.Asp36His) variant causes a missense change. The variant allele was found at a frequency of 0.000668 in 1,511,952 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00071 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 8 hom. )

Consequence

ACTN3
NM_001104.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.89

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027109325).

BP6

Variant 11-66547043-G-C is Benign according to our data. Variant chr11-66547043-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3033952.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN3	NM_001104.4 linkuse as main transcript	c.106G>C	p.Asp36His	missense_variant	1/21	ENST00000513398.2
ACTN3	NM_001258371.3 linkuse as main transcript	c.276+257G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ACTN3	ENST00000513398.2 linkuse as main transcript	c.106G>C	p.Asp36His	missense_variant	1/21	1	NM_001104.4	P1
ACTN3	ENST00000502692.5 linkuse as main transcript	c.276+257G>C		intron_variant		2
ACTN3	ENST00000511191.1 linkuse as main transcript	c.106G>C	p.Asp36His	missense_variant, NMD_transcript_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

109

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00656

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00119

AC:

199

AN:

167724

Hom.:

AF XY:

0.00116

AC XY:

103

AN XY:

89002

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00565

Gnomad SAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00488

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00238

GnomAD4 exome

AF:

0.000663

AC:

902

AN:

1359628

Hom.:

Cov.:

AF XY:

0.000643

AC XY:

428

AN XY:

665288

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0122

Gnomad4 SAS exome

AF:

0.000273

Gnomad4 FIN exome

AF:

0.00458

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.000808

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152324

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00638

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000975

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00106

AC:

126

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ACTN3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Pathogenic

0.25

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.027

Sift4G

Uncertain

0.0090

Polyphen

0.98

Vest4

0.76

MVP

0.68

GERP RS

3.3

Varity_R

0.25

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over