12-57243855-C-T

Variant names:

• chr12-57243855-C-T
• rs762866281
• NM_145064.3:c.1052G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145064.3(STAC3):​c.1052G>A​(p.Arg351His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R351L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAC3 NM_145064.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• Publications: 1 publications found

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]

STAC3 Gene-Disease associations (from GenCC):

• Bailey-Bloch congenital myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, G2P

ENSG00000295078 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40819803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAC3	NM_145064.3	c.1052G>A	p.Arg351His	missense_variant	Exon 12 of 12	ENST00000332782.7	NP_659501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAC3	ENST00000332782.7	c.1052G>A	p.Arg351His	missense_variant	Exon 12 of 12	2	NM_145064.3	ENSP00000329200.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	.;T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	.;L;.
PhyloP100		5.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.026	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.45
MutPred		0.65		.;Gain of catalytic residue at K352 (P = 0);.;
MVP		0.29
MPC		1.2
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.74
gMVP		0.61
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762866281; hg19: chr12-57637638;