rs1553255354

Positions:

• chr1-229431843-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP2 PP3 PM2_Supporting PS4_Supporting PM5 PS2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.868G>C variant in ACTA1 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 290 (legacy nomenclature: p.Asp288His). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 2 probands , including one with a muscle biopsy containing nemaline rods (PS4_Supporting, PP4_Moderate; PMIDs: 29565416, 28516742). In both individuals, the variant has been identified as a de novo occurrence with confirmed parental relationships (PS2). Another missense variant c.868G>A, p.Asp290Asn (PMIDs: 19562689, 27242277) in the same codon has been classified as pathogenic for AD nemaline myopathy by the ClinGen Congenital Myopathies VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM5, PP4_Moderate, PS4_Supporting, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 1; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA345145962/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.86

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 12 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.868G>C	p.Asp290His	missense_variant	6/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.868G>C	p.Asp290His	missense_variant	6/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.868G>C	p.Asp290His	missense_variant	6/7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.733G>C	p.Asp245His	missense_variant	5/6			ENSP00000508084.1
ENSG00000290037	ENST00000702606.1	n.*4C>G		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 04, 2018

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2016

- -

Alpha-actinopathy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 27, 2024

The c.868G>C variant in ACTA1 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 290 (legacy nomenclature: p.Asp288His). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 2 probands , including one with a muscle biopsy containing nemaline rods (PS4_Supporting, PP4_Moderate; PMIDs: 29565416, 28516742). In both individuals, the variant has been identified as a de novo occurrence with confirmed parental relationships (PS2). Another missense variant c.868G>A, p.Asp290Asn (PMIDs: 19562689, 27242277) in the same codon has been classified as pathogenic for AD nemaline myopathy by the ClinGen Congenital Myopathies VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM5, PP4_Moderate, PS4_Supporting, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 1; 08/27/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.2	D;.
REVEL	Pathogenic	0.98
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.87		Loss of ubiquitination at K286 (P = 0.0768);.;
MVP		0.99
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1553255354; hg19: chr1-229567590;