NM_001104.4:c.235C>A

Variant names:

• chr11-66551326-C-A
• rs369975190
• NM_001104.4:c.235C>A

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.235C>A​(p.Leu79Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. L79F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTN3 NM_001104.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• 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, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.235C>A	p.Leu79Ile	missense_variant	Exon 2 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.364C>A	p.Leu122Ile	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.235C>A	p.Leu79Ile	missense_variant	Exon 2 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000502692.5	c.364C>A	p.Leu122Ile	missense_variant	Exon 2 of 21	2		ENSP00000422007.1
ACTN3	ENST00000511191.1	n.*202C>A		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000426236.1
ACTN3	ENST00000511191.1	n.*202C>A		3_prime_UTR_variant	Exon 2 of 5	5		ENSP00000426236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Pathogenic	0.85	D;D
PhyloP100		6.2
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.95	.;P
Vest4		0.87
MVP		0.49
GERP RS		5.0
Varity_R		0.25
gMVP		0.43

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: rs369975190; hg19: chr11-66318797;