11-66551312-G-A

Variant names:

• chr11-66551312-G-A
• rs202165715
• NM_001104.4:c.221G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.221G>A	p.Arg74His	missense_variant	Exon 2 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.350G>A	p.Arg117His	missense_variant	Exon 2 of 21		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2	c.221G>A	p.Arg74His	missense_variant	Exon 2 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000502692.5	c.350G>A	p.Arg117His	missense_variant	Exon 2 of 21	2		ENSP00000422007.1
ACTN3	ENST00000511191.1	n.*188G>A		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000426236.1
ACTN3	ENST00000511191.1	n.*188G>A		3_prime_UTR_variant	Exon 2 of 5	5		ENSP00000426236.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 41 AN: 245892 AF XY: 0.000181

Gnomad AFR exome AF: 0.0000656

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000333

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000510 AC: 744 AN: 1459196 Hom.: 0 Cov.: 31 AF XY: 0.000489 AC XY: 355 AN XY: 725546

African (AFR) AF: 0.0000299 AC: 1 AN: 33416

American (AMR) AF: 0.0000451 AC: 2 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000627 AC: 696 AN: 1110806

Other (OTH) AF: 0.000680 AC: 41 AN: 60324

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74356

African (AFR) AF: 0.000121 AC: 5 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000378 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Pathogenic	0.82	D;D
PhyloP100		10
PrimateAI	Uncertain	0.77	T
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	.;D
Vest4		0.82
MVP		0.87
GERP RS		5.0
Varity_R		0.30
gMVP		0.50

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

Other links and lift over

dbSNP: rs202165715; hg19: chr11-66318783; COSMIC: COSV101557899;