NM_145064.3:c.560T>C

Variant names:

• chr12-57246847-A-G
• rs1461373398
• NM_145064.3:c.560T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145064.3(STAC3):​c.560T>C​(p.Met187Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. M187K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STAC3 NM_145064.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.28
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAC3	NM_145064.3	MANE Select	c.560T>C	p.Met187Thr	missense	Exon 6 of 12	NP_659501.1
	STAC3	NM_001286257.2		c.2T>C	p.Met1?	start_lost	Exon 3 of 9	NP_001273186.1
	STAC3	NM_001286256.2		c.443T>C	p.Met148Thr	missense	Exon 5 of 11	NP_001273185.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAC3	ENST00000332782.7	TSL:2 MANE Select	c.560T>C	p.Met187Thr	missense	Exon 6 of 12	ENSP00000329200.2
	STAC3	ENST00000554578.5	TSL:1	c.443T>C	p.Met148Thr	missense	Exon 5 of 11	ENSP00000452068.1
	STAC3	ENST00000557176.5	TSL:1	n.2T>C		non_coding_transcript_exon	Exon 3 of 8	ENSP00000450740.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461750 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727190

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.8	L
PhyloP100		8.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.93	P
Vest4		0.81
MutPred		0.36		Gain of catalytic residue at V185 (P = 0)
MVP		0.92
MPC		0.91
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.64
gMVP		0.62
Mutation Taster		=28/172	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1461373398; hg19: chr12-57640630;