rs869312739

Variant names:

• chr1-229432295-C-A
• rs869312739
• NM_001100.4:c.591G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-229432295-C-A
• chr1-229432295-C-G
• chr1-229432295-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001100.4(ACTA1):​c.591G>T​(p.Glu197Asp) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E197K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.07

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 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr1-229432297-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3600996.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.892
• PP5: Variant 1-229432295-C-A is Pathogenic according to our data. Variant chr1-229432295-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 224412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229432295-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.591G>T	p.Glu197Asp	missense_variant	Exon 4 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.591G>T	p.Glu197Asp	missense_variant	Exon 4 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.591G>T	p.Glu197Asp	missense_variant	Exon 4 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.456G>T	p.Glu152Asp	missense_variant	Exon 3 of 6			ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Apr 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 224412). This missense change has been observed in individuals with autosomal dominant ACTA1-related disorders (PMID: 25938801, 30732915). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 197 of the ACTA1 protein (p.Glu197Asp). -

Progressive scapulohumeroperoneal distal myopathy Pathogenic:1

Jul 16, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in a parent and child with distal myopathy with nemaline rods on muscle biopsy (Hernandez-Lain et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25470062, 25938801, 30732915, 27519468, 29433794) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.60
Sift4G	Benign	0.085	T
Polyphen		0.0	B
Vest4		0.91
MutPred		0.66		Gain of ubiquitination at K193 (P = 0.1106);
MVP		0.96
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.88
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs869312739; hg19: chr1-229568042;