rs768144106

chr1-229432426-C-Achr1-229432426-C-Gchr1-229432426-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_001100.4(ACTA1):c.460G>T(p.Val154Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000664 in 150,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V154A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACTA1
NM_001100.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.76

Variant links:

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]

ACTA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PS1

Transcript NM_001100.4 (ACTA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 224666

PM1

In a hotspot region, there are 5 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-229432425-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 532771.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, ACTA1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 1-229432426-C-A is Pathogenic according to our data. Variant chr1-229432426-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 855039.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA1	NM_001100.4 linkuse as main transcript	c.460G>T	p.Val154Leu	missense_variant	4/7	ENST00000366684.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ACTA1	ENST00000366684.7 linkuse as main transcript	c.460G>T	p.Val154Leu	missense_variant	4/7	1	NM_001100.4	P1
ACTA1	ENST00000366683.4 linkuse as main transcript	c.460G>T	p.Val154Leu	missense_variant	4/7	5
ACTA1	ENST00000684723.1 linkuse as main transcript	c.325G>T	p.Val109Leu	missense_variant	3/6

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1458170

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000664

AC:

AN:

150682

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73460

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Actin accumulation myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 154 of the ACTA1 protein (p.Val154Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive ACTA1-related conditions (PMID: 25182138, 31321302; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 855039). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTA1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

Cadd

Pathogenic

Dann

Benign

0.91

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.0

H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.4

N;.

REVEL

Pathogenic

0.96

Sift4G

Uncertain

0.017

D;D

Polyphen

0.62

P;.

Vest4

0.72

MutPred

0.79

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.99

ClinPred

1.0

GERP RS

4.4

Varity_R

0.97

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over