11-66547041-G-C

Variant names:

• chr11-66547041-G-C
• rs1341984494
• NM_001104.4:c.104G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001104.4(ACTN3):​c.104G>C​(p.Arg35Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000147 in 1,359,464 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. R35H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ACTN3 NM_001104.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.90
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.104G>C	p.Arg35Pro	missense_variant	Exon 1 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.276+255G>C		intron_variant	Intron 1 of 20		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2	c.104G>C	p.Arg35Pro	missense_variant	Exon 1 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000511191.1	n.104G>C		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000426236.1
ACTN3	ENST00000502692.5	c.276+255G>C		intron_variant	Intron 1 of 20	2		ENSP00000422007.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000147 AC: 20 AN: 1359464 Hom.: 0 Cov.: 32 AF XY: 0.0000120 AC XY: 8 AN XY: 665220

African (AFR) AF: 0.00 AC: 0 AN: 30048

American (AMR) AF: 0.00 AC: 0 AN: 28528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19750

East Asian (EAS) AF: 0.00 AC: 0 AN: 38478

South Asian (SAS) AF: 0.00 AC: 0 AN: 69616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4350

European-Non Finnish (NFE) AF: 0.0000188 AC: 20 AN: 1063712

Other (OTH) AF: 0.00 AC: 0 AN: 55686

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.91	D
PhyloP100		5.9
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.89
MVP		0.75
GERP RS		3.4
PromoterAI		-0.061	Neutral
Varity_R		0.45

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: rs1341984494; hg19: chr11-66314512;