1-229433007-C-A

Position:

• chr1-229433007-C-A

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001100.4(ACTA1):​c.109G>T​(p.Val37Leu) 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V37A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.88

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 21 ACMG points.

• PS1: Transcript NM_001100.4 (ACTA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-229433006-A-G is described in Lovd as [Pathogenic].
• 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). GenCC has associacion of 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, 0.981
• PP5: Variant 1-229433007-C-A is Pathogenic according to our data. Variant chr1-229433007-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229433007-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.109G>T	p.Val37Leu	missense_variant	2/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.109G>T	p.Val37Leu	missense_variant	2/7	1	NM_001100.4	ENSP00000355645	P1
ACTA1	ENST00000366683.4	c.109G>T	p.Val37Leu	missense_variant	2/7	5		ENSP00000355644
ACTA1	ENST00000684723.1	c.-6-127G>T		intron_variant				ENSP00000508084

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Actin accumulation myopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	provider interpretation	Pediatric Department, Peking University First Hospital	Apr 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2017	This variant has been reported in an individual affected with nemaline myopathy (PMID: 19562689, 23394784). In summary, this variant is a rare missense change that has been reported in multiple affected individuals. For these reasons, it has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different nucleotide change (c.109G>C) that produces the same amino acid change as this variant (p.Val37Leu) has been reported in multiple individuals affected with nemaline myopathy (PMID: 19562689, 12921789, 15236405). In 2 of these cases this variant was reported to arise de novo (PMID: 19562689, 12921789, 15236405). The c.109G>C sequence change has also been reported as p.Val35Leu. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 37 of the ACTA1 protein (p.Val37Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously described as disease-causing in the literature, as has another mutation causing the same amino acid substitution. It has been identified once in our laboratory as a de novo mutation in a 1-month-old female with nemaline myopathy, hypotonia, respiratory distress, and cardiac arrest -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2024

Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19562689, 22759684, 23394784, 25326635, 35081925, 28973083, 12921789, 15236405) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.62	P;.
Vest4		0.85
MutPred		0.92		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.97
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.90
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553255521; hg19: chr1-229568754;