12-57243911-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_145064.3(STAC3):​c.997-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

STAC3
NM_145064.3 splice_acceptor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 7.44
Variant links:
Genes affected
STAC3 (HGNC:28423): (SH3 and cysteine rich domain 3) The protein encoded by this gene is a component of the excitation-contraction coupling machinery of muscles. This protein is a member of the Stac gene family and contains an N-terminal cysteine-rich domain and two SH3 domains. Mutations in this gene are a cause of Native American myopathy. [provided by RefSeq, Nov 2013]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.41369864 fraction of the gene.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-57243911-C-A is Pathogenic according to our data. Variant chr12-57243911-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 691283.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-57243911-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STAC3NM_145064.3 linkc.997-1G>T splice_acceptor_variant, intron_variant Intron 11 of 11 ENST00000332782.7 NP_659501.1 Q96MF2-1A0A024RB38

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STAC3ENST00000332782.7 linkc.997-1G>T splice_acceptor_variant, intron_variant Intron 11 of 11 2 NM_145064.3 ENSP00000329200.2 Q96MF2-1
STAC3ENST00000554578.5 linkc.880-1G>T splice_acceptor_variant, intron_variant Intron 10 of 10 1 ENSP00000452068.1 Q96MF2-2
STAC3ENST00000557176.5 linkn.*57-1G>T splice_acceptor_variant, intron_variant Intron 7 of 7 1 ENSP00000450740.1 G3V2L9
STAC3ENST00000546246.2 linkc.439-1G>T splice_acceptor_variant, intron_variant Intron 8 of 8 2 ENSP00000441515.2 Q96MF2-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461454
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726988
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Bailey-Bloch congenital myopathy Pathogenic:1Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jul 16, 2024
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Uncertain
0.91
D
GERP RS
4.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.79
Position offset: -13
DS_AL_spliceai
0.99
Position offset: -1

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.

Other links and lift over

dbSNP: rs779483367; hg19: chr12-57637694; API