1-229433067-C-T

Position:

• chr1-229433067-C-T

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.49G>A​(p.Gly17Ser) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89

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 13 ACMG points.

• PM1: In a hotspot region, there are 2 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 chr1-229433067-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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). 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, 0.957
• PP5: Variant 1-229433067-C-T is Pathogenic according to our data. Variant chr1-229433067-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 951759.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.49G>A	p.Gly17Ser	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.49G>A	p.Gly17Ser	missense_variant	2/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.49G>A	p.Gly17Ser	missense_variant	2/7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.-6-187G>A		intron_variant				ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2019

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 17 of the ACTA1 protein (p.Gly17Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant has been observed to be de novo in an individual affected with nemaline myopathy (PMID: 29274205). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly17 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10508519, 15226407, 17227580, 20621480, 23294764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	D;N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.080	T;T
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.80		Loss of glycosylation at S16 (P = 0.0243);Loss of glycosylation at S16 (P = 0.0243);
MVP		1.0
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.95
gMVP		0.97

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: rs121909521; hg19: chr1-229568814;