chr12-57243884-C-G

Position:

• chr12-57243884-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_145064.3(STAC3):​c.1023G>C​(p.Ala341=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,613,814 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (30 hom.)
• Consequence: STAC3 NM_145064.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.27

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-57243884-C-G is Benign according to our data. Variant chr12-57243884-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 262570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00431 (656/152174) while in subpopulation AMR AF= 0.00444 (68/15302). AF 95% confidence interval is 0.00376. There are 3 homozygotes in gnomad4. There are 380 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAC3	NM_145064.3	c.1023G>C	p.Ala341=	synonymous_variant	12/12	ENST00000332782.7	NP_659501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAC3	ENST00000332782.7	c.1023G>C	p.Ala341=	synonymous_variant	12/12	2	NM_145064.3	ENSP00000329200	P1
STAC3	ENST00000554578.5	c.906G>C	p.Ala302=	synonymous_variant	11/11	1		ENSP00000452068
STAC3	ENST00000557176.5	c.*83G>C		3_prime_UTR_variant, NMD_transcript_variant	8/8	1		ENSP00000450740
STAC3	ENST00000546246.2	c.465G>C	p.Ala155=	synonymous_variant	9/9	2		ENSP00000441515

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 656 AN: 152056 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00449 AC: 1124 AN: 250332 Hom.: 10 AF XY: 0.00466 AC XY: 632 AN XY: 135510

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00387 AC: 5654 AN: 1461640 Hom.: 30 Cov.: 32 AF XY: 0.00390 AC XY: 2835 AN XY: 727108

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00278

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.0208

Gnomad4 NFE exome AF: 0.00357

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152174 Hom.: 3 Cov.: 32 AF XY: 0.00511 AC XY: 380 AN XY: 74400

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.0222

Gnomad4 NFE AF: 0.00416

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00311

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	STAC3: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 03, 2017

- -

STAC3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bailey-Bloch congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.2
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61747067; hg19: chr12-57637667;