rs121909527

chr1-229433109-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_001100.4(ACTA1):c.7G>T(p.Asp3Tyr) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.55

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ACTA1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 1-229433109-C-A is Pathogenic according to our data. Variant chr1-229433109-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 18287.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-229433109-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA1	NM_001100.4	c.7G>T	p.Asp3Tyr	missense_variant	2/7	ENST00000366684.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA1	ENST00000366684.7	c.7G>T	p.Asp3Tyr	missense_variant	2/7	1	NM_001100.4	P1
ACTA1	ENST00000366683.4	c.7G>T	p.Asp3Tyr	missense_variant	2/7	5
ACTA1	ENST00000684723.1	c.-6-229G>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.56	N;N
REVEL	Pathogenic	0.74
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.57	P;.
Vest4		0.89
MutPred		0.60		Loss of disorder (P = 0.0413);Loss of disorder (P = 0.0413);
MVP		0.99
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.68
gMVP		0.95

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: rs121909527; hg19: chr1-229568856;