chr1-229431633-G-A

Position:

• chr1-229431633-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001100.4(ACTA1):​c.1000C>T​(p.Pro334Ser) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P334R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 8.09

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]

ENSG00000290037 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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, 7 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 chr1-229431632-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1031829.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA1. . Gene score misZ: 4.5292 (greater than the threshold 3.09). Trascript score misZ: 6.088 (greater than threshold 3.09). The gene has 154 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. GenCC has associacion of the gene with 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, 0.95
• PP5: Variant 1-229431633-G-A is Pathogenic according to our data. Variant chr1-229431633-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18291.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-229431633-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.1000C>T	p.Pro334Ser	missense_variant	7/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.1000C>T	p.Pro334Ser	missense_variant	7/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000684723.1	c.865C>T	p.Pro289Ser	missense_variant	6/6			ENSP00000508084.1
ACTA1	ENST00000366683.4	c.991-69C>T		intron_variant		5		ENSP00000355644.4
ENSG00000290037	ENST00000702606.1	n.268G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

Experimental studies have shown that this missense change affects ACTA1 function (PMID: 19206168). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro334 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt ACTA1 protein function. ClinVar contains an entry for this variant (Variation ID: 18291). This variant is also known as p.Pro332Ser. This missense change has been observed in individual(s) with autosomal dominant congenital fiber type disproportion (PMID: 15468086). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 334 of the ACTA1 protein (p.Pro334Ser). -

Progressive scapulohumeroperoneal distal myopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2004

- -

Congenital myopathy with fiber type disproportion Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.92
Sift4G	Benign	0.087	T;T
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.82		Loss of catalytic residue at P334 (P = 0.0085);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.99

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: rs121909531; hg19: chr1-229567380;