chr1-229431506-C-G

Position:

• chr1-229431506-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS2 PP4_Moderate PP2 PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_001100.4:c.1127G>C in ACTA1 is a missense variant predicted to cause substitution of cysteine by serine at amino acid 376 (p.Cys376Ser) in exon 7/7. The variant is absent from gnomAD v2.1.1 with adequate coverage (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.946, which is above the threshold necessary to apply PP3. In addition, 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). The Z-score in gnomAD v2.1.1 is 4.53 which is above the threshold necessary to apply PP2. This variant has been reported in two probands with congenital nemaline myopathy (PS4_Supporting, PP4_Moderate PMID:25890230,19562689), and as a de novo observation with confirmed parental relationships in one of the probands (PS2, PMID:25890230). In summary, the variant meets the criteria to be classified as Pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PP4_Moderate, PS4_Supporting, PP2, PP3, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA345144077/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1
• 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 10 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.
• 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.1127G>C	p.Cys376Ser	missense_variant	7/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.1127G>C	p.Cys376Ser	missense_variant	7/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.1049G>C	p.Cys350Ser	missense_variant	7/7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.992G>C	p.Cys331Ser	missense_variant	6/6			ENSP00000508084.1
ENSG00000290037	ENST00000702606.1	n.141C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Alpha-actinopathy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 27, 2024

The variant NM_001100.4:c.1127G>C in ACTA1 is a missense variant predicted to cause substitution of cysteine by serine at amino acid 376 (p.Cys376Ser) in exon 7/7. The variant is absent from gnomAD v2.1.1 with adequate coverage (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.946, which is above the threshold necessary to apply PP3. In addition, 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). The Z-score in gnomAD v2.1.1 is 4.53 which is above the threshold necessary to apply PP2. This variant has been reported in two probands with congenital nemaline myopathy (PS4_Supporting, PP4_Moderate PMID:25890230,19562689), and as a de novo observation with confirmed parental relationships in one of the probands (PS2, PMID:25890230). In summary, the variant meets the criteria to be classified as Pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PP4_Moderate, PS4_Supporting, PP2, PP3, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.95
Sift4G	Uncertain	0.010	D;D
Polyphen		0.94	P;.
Vest4		0.94
MutPred		0.77		Gain of disorder (P = 0.0026);.;
MVP		0.99
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.95
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-229567253;