rs121909530

Variant names:

• chr1-229432134-A-G
• rs121909530
• NM_001100.4:c.668T>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001100.4(ACTA1):​c.668T>C​(p.Leu223Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L223V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 9.16

Genes affected

ACTA1 (HGNC:129): (actin alpha 1, skeletal muscle) The product encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Mutations in this gene cause a variety of myopathies, including nemaline myopathy, congenital myopathy with excess of thin myofilaments, congenital myopathy with cores, and congenital myopathy with fiber-type disproportion, diseases that lead to muscle fiber defects with manifestations such as hypotonia. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001100.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-229432135-G-C is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the ACTA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 154 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.5292 (above the threshold of 3.09). Trascript score misZ: 6.088 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital myopathy with excess of thin filaments, nemaline myopathy 3, intermediate nemaline myopathy, typical nemaline myopathy, congenital fiber-type disproportion myopathy, severe congenital nemaline myopathy, rigid spine syndrome, zebra body myopathy, childhood-onset nemaline myopathy, congenital myopathy 2c, severe infantile, autosomal dominant, alpha-actinopathy, progressive scapulohumeroperoneal distal myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 1-229432134-A-G is Pathogenic according to our data. Variant chr1-229432134-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18290.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}. Variant chr1-229432134-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.668T>C	p.Leu223Pro	missense_variant	Exon 5 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.668T>C	p.Leu223Pro	missense_variant	Exon 5 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.668T>C	p.Leu223Pro	missense_variant	Exon 5 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.533T>C	p.Leu178Pro	missense_variant	Exon 4 of 6			ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myopathy with fiber type disproportion Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 12, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy 2c, severe infantile, autosomal dominant Pathogenic:1

Nov 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Actin accumulation myopathy Uncertain:1

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTA1 protein function. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 19206168). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 18290). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 223 of the ACTA1 protein (p.Leu223Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital fibre type disproportion (PMID: 15468086). This variant is also known as p.Leu221Pro. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.94
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.98
MutPred		0.84		Loss of stability (P = 0.0017);
MVP		0.99
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.98
gMVP		1.0

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

Other links and lift over

dbSNP: rs121909530; hg19: chr1-229567881;