chr12-57243834-G-A

Position:

• chr12-57243834-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145064.3(STAC3):​c.1073C>T​(p.Thr358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAC3 NM_145064.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11253965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAC3	NM_145064.3	c.1073C>T	p.Thr358Ile	missense_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.1073C>T	p.Thr358Ile	missense_variant	12/12	2	NM_145064.3	ENSP00000329200	P1
STAC3	ENST00000554578.5	c.956C>T	p.Thr319Ile	missense_variant	11/11	1		ENSP00000452068
STAC3	ENST00000557176.5	c.*133C>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	1		ENSP00000450740
STAC3	ENST00000546246.2	c.515C>T	p.Thr172Ile	missense_variant	9/9	2		ENSP00000441515

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bailey-Bloch congenital myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with STAC3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 358 of the STAC3 protein (p.Thr358Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.027	.;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.
MutationTaster	Benign	0.64	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.2	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.13	.;B;.
Vest4		0.17
MutPred		0.62		.;Gain of catalytic residue at L355 (P = 0);.;
MVP		0.17
MPC		0.36
ClinPred		0.24	T
GERP RS		3.8
Varity_R		0.15
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-57637617;