rs140291094

Positions:

• chr12-57244322-C-G
• chr12-57244322-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_145064.3(STAC3):​c.851G>C​(p.Trp284Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: STAC3 NM_145064.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.72

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 12-57244322-C-G is Pathogenic according to our data. Variant chr12-57244322-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57244322-C-G is described in Lovd as [Pathogenic]. Variant chr12-57244322-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAC3	NM_145064.3	c.851G>C	p.Trp284Ser	missense_variant	10/12	ENST00000332782.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAC3	ENST00000332782.7	c.851G>C	p.Trp284Ser	missense_variant	10/12	2	NM_145064.3	P1
STAC3	ENST00000554578.5	c.734G>C	p.Trp245Ser	missense_variant	9/11	1
STAC3	ENST00000557176.5	c.226G>C	p.Gly76Arg	missense_variant, NMD_transcript_variant	6/8	1
STAC3	ENST00000546246.2	c.293G>C	p.Trp98Ser	missense_variant	7/9	2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251398 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135870

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22 AN XY: 727226

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.0000671

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: 0.00000450

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74498

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000453

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bailey-Bloch congenital myopathy Pathogenic:13 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Oct 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28777491, 23736855, PS4_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 28777491, PM3_M) and co-segregated with Myopathy, congenital, Baily-Bloch in multiple affected family members (PMID: 28777491, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.886, 3CNET: 0.861, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000117, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a compound heterozygous and homozygous change in individuals with Bailey-Bloch congenital myopathy (PMID: 30168660, 23736855, 27621462, 28777491, 28003463). Functional studies have shown this variant impairs normal STAC3 protein function (PMID: 23736855). The c.851G>C (p.Trp284Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.00012% (33/282798). It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.851G>C (p.Trp284Ser) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 15, 2018	The homozygous p.Trp284Ser variant was identified by our study in one individual with Native American myopathy. This variant is pathogenic based on multiple reports in ClinVar and the literature. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 19, 2023	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 284 of the STAC3 protein (p.Trp284Ser). This variant is present in population databases (rs140291094, gnomAD 0.1%). This missense change has been observed in individual(s) with Native American myopathy, Carey–Fineman–Ziter syndrome and Moebius syndrome (PMID: 23736855, 28777491). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88744). 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 expected to disrupt STAC3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAC3 function (PMID: 23736855). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratoire Génétique Moléculaire, CHRU TOURS	May 23, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 05, 2022	Variant summary: STAC3 c.851G>C (p.Trp284Ser) results in a non-conservative amino acid change located in the SH3 domain (IPR001452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251398 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. c.851G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Bailey-Bloch Congenital Myopathy and has been found to segregrate with the disease phenotype in multiple families affected with the disorder (e.g. Horstick_2013, Telegrafi_2017, Zaharieva_2018). These data indicate that the variant is very likely to be associated with disease. At least one experimental study examining the effect of the variant protein in a zebrafish model system found that it diminished excitation-contraction coupling in fast twitch muscle, suggesting that the variant affects normal protein function (e.g. Horstick_2013). Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2022	Published functional studies demonstrate a damaging effect (reduction of amount, organization, stability, and voltage sensitivity of calcium channels) (Linsley et al., 2017; Horstick et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28003463, 27621462, 28777491, 28676249, 29078335, 23736855, 30168660, 30872186, 34374989, 35205385, 35912995, 35481653, 34208776, 33827624, 33060286) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	.;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-13	D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		1.0
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs140291094; hg19: chr12-57638105;