1-229431727-C-G

Position:

• chr1-229431727-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001100.4(ACTA1):​c.984G>C​(p.Lys328Asn) variant causes a missense change involving the alteration of a non-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). Synonymous variant affecting the same amino acid position (i.e. K328K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.35

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.

• PM1: In a hotspot region, there are 4 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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA1. . Gene score misZ 4.5292 (greater than the threshold 3.09). Trascript score misZ 6.088 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.964
• PP5: Variant 1-229431727-C-G is Pathogenic according to our data. Variant chr1-229431727-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 50318.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-229431727-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.984G>C	p.Lys328Asn	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.984G>C	p.Lys328Asn	missense_variant	6/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.984G>C	p.Lys328Asn	missense_variant	6/7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.849G>C	p.Lys283Asn	missense_variant	5/6			ENSP00000508084.1
ENSG00000290037	ENST00000702606.1	n.362C>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: no assertion criteria provided

Submissions by phenotype

Congenital myopathy 2c, severe infantile, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 03, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Benign	0.029
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.058	T;T
Polyphen		0.0	B;.
Vest4		0.82
MutPred		0.92		Loss of ubiquitination at K328 (P = 0.0446);.;
MVP		0.99
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.98
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

LitVar

Other links and lift over

dbSNP: rs398122936; hg19: chr1-229567474;