12-57243911-C-A

Variant names:

• chr12-57243911-C-A
• rs779483367
• NM_145064.3:c.997-1G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

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: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.44

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]

ACMG classification

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
STAC3	NM_145064.3	c.997-1G>T		splice_acceptor_variant, intron_variant	Intron 11 of 11	ENST00000332782.7	NP_659501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAC3	ENST00000332782.7	c.997-1G>T		splice_acceptor_variant, intron_variant	Intron 11 of 11	2	NM_145064.3	ENSP00000329200.2
STAC3	ENST00000554578.5	c.880-1G>T		splice_acceptor_variant, intron_variant	Intron 10 of 10	1		ENSP00000452068.1
STAC3	ENST00000557176.5	n.*57-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 7	1		ENSP00000450740.1
STAC3	ENST00000546246.2	c.439-1G>T		splice_acceptor_variant, intron_variant	Intron 8 of 8	2		ENSP00000441515.2

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

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:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Bailey-Bloch congenital myopathy Pathogenic:1 Other:1

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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

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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

Other links and lift over

dbSNP: rs779483367; hg19: chr12-57637694;