rs76823783

Variant names:

• chr12-57245219-G-A
• rs76823783
• NM_145064.3:c.604-8C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_145064.3(STAC3):​c.604-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 1,613,798 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (186 hom.)
• Consequence: STAC3 NM_145064.3 splice_region, intron
• Scores: Splicing: ADA: 0.0008489
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.14
• Publications: 2 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-57245219-G-A is Benign according to our data. Variant chr12-57245219-G-A is described in ClinVar as Benign. ClinVar VariationId is 262576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0659 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145064.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAC3	NM_145064.3	MANE Select	c.604-8C>T		splice_region intron	N/A	NP_659501.1
	STAC3	NM_001286256.2		c.487-8C>T		splice_region intron	N/A	NP_001273185.1
	STAC3	NM_001286257.2		c.46-8C>T		splice_region intron	N/A	NP_001273186.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAC3	ENST00000332782.7	TSL:2 MANE Select	c.604-8C>T		splice_region intron	N/A	ENSP00000329200.2
	STAC3	ENST00000554578.5	TSL:1	c.487-8C>T		splice_region intron	N/A	ENSP00000452068.1
	STAC3	ENST00000557176.5	TSL:1	n.46-254C>T		intron	N/A	ENSP00000450740.1

Frequencies

GnomAD3 genomes AF: 0.00891 AC: 1355 AN: 152124 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00908

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0719

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.0109 AC: 2737 AN: 250826 AF XY: 0.0111

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00449

Gnomad EAS exome AF: 0.0666

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00576

Gnomad OTH exome AF: 0.00639

GnomAD4 exome AF: 0.00937 AC: 13692 AN: 1461556 Hom.: 186 Cov.: 31 AF XY: 0.00952 AC XY: 6920 AN XY: 727076

African (AFR) AF: 0.00974 AC: 326 AN: 33474

American (AMR) AF: 0.00148 AC: 66 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00574 AC: 150 AN: 26120

East Asian (EAS) AF: 0.0728 AC: 2889 AN: 39686

South Asian (SAS) AF: 0.0185 AC: 1598 AN: 86194

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53396

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.00709 AC: 7884 AN: 1111832

Other (OTH) AF: 0.0107 AC: 648 AN: 60382

GnomAD4 genome AF: 0.00892 AC: 1358 AN: 152242 Hom.: 22 Cov.: 32 AF XY: 0.00993 AC XY: 739 AN XY: 74434

African (AFR) AF: 0.00912 AC: 379 AN: 41536

American (AMR) AF: 0.00170 AC: 26 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.0719 AC: 371 AN: 5160

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4822

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00657 AC: 447 AN: 68020

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00610 Hom.: 4

Bravo AF: 0.00940

Asia WGS AF: 0.0510 AC: 177 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Bailey-Bloch congenital myopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		3.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00085
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.020		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: rs76823783; hg19: chr12-57639002; COSMIC: COSV60414248; COSMIC: COSV60414248;