rs1553255444

Positions:

• chr1-229432407-CCGTCGCCGGAGTCCAGCA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_001100.4(ACTA1):​c.461_478delTGCTGGACTCCGGCGACG​(p.Val154_Asp159del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V154V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 NM_001100.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.81

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001100.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001100.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-229432407-CCGTCGCCGGAGTCCAGCA-C is Pathogenic according to our data. Variant chr1-229432407-CCGTCGCCGGAGTCCAGCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 464124.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.461_478delTGCTGGACTCCGGCGACG	p.Val154_Asp159del	disruptive_inframe_deletion	4/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.461_478delTGCTGGACTCCGGCGACG	p.Val154_Asp159del	disruptive_inframe_deletion	4/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.461_478delTGCTGGACTCCGGCGACG	p.Val154_Asp159del	disruptive_inframe_deletion	4/7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.326_343delTGCTGGACTCCGGCGACG	p.Val109_Asp114del	disruptive_inframe_deletion	3/6			ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

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

Jul 14, 2023

This variant has not been reported in the literature in individuals affected with ACTA1-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACTA1 protein in which other variant(s) (p.Val154Leu) have been determined to be pathogenic (PMID: 25182138, 27854218; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 464124). This variant is not present in population databases (gnomAD no frequency). This variant, c.461_478del, results in the deletion of 6 amino acid(s) of the ACTA1 protein (p.Val154_Asp159del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553255444; hg19: chr1-229568154;