dbSNP rs115276341: STAC3:p.Asn281Ser (chr12-57244331-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_145064.3(STAC3):c.842A>G(p.Asn281Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,614,140 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N281N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0040 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 5 hom. )

Consequence

STAC3
NM_145064.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.03

Publications

8 publications found

Variant links:

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: PanelApp Australia, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

STAC3 links:

ENSG00000295078 (HGNC:):

ENSG00000295078 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010758579).

BP6

Variant 12-57244331-T-C is Benign according to our data. Variant chr12-57244331-T-C is described in ClinVar as Benign. ClinVar VariationId is 262577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00404 (616/152288) while in subpopulation AFR AF = 0.0138 (573/41560). AF 95% confidence interval is 0.0129. There are 2 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STAC3	NM_145064.3	MANE Select	c.842A>G	p.Asn281Ser	missense	Exon 10 of 12	NP_659501.1	Q96MF2-1
STAC3	NM_001286256.2		c.725A>G	p.Asn242Ser	missense	Exon 9 of 11	NP_001273185.1	Q96MF2-2
STAC3	NM_001286257.2		c.284A>G	p.Asn95Ser	missense	Exon 7 of 9	NP_001273186.1	Q96MF2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STAC3	ENST00000332782.7	TSL:2 MANE Select	c.842A>G	p.Asn281Ser	missense	Exon 10 of 12	ENSP00000329200.2	Q96MF2-1
STAC3	ENST00000554578.5	TSL:1	c.725A>G	p.Asn242Ser	missense	Exon 9 of 11	ENSP00000452068.1	Q96MF2-2
STAC3	ENST00000557176.5	TSL:1	n.217A>G		non_coding_transcript_exon	Exon 6 of 8	ENSP00000450740.1	G3V2L9

Frequencies

GnomAD3 genomes

AF:

0.00404

AC:

615

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000915

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00127

AC:

319

AN:

251392

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000501

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000695

AC:

1016

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000650

AC XY:

473

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0149

AC:

498

AN:

33480

American (AMR)

AF:

0.000402

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000375

AC:

417

AN:

1112012

Other (OTH)

AF:

0.000911

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

130

194

259

324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00404

AC:

616

AN:

152288

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

312

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0138

AC:

573

AN:

41560

American (AMR)

AF:

0.000914

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68006

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000894

Hom.:

Bravo

AF:

0.00458

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00163

AC:

198

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bailey-Bloch congenital myopathy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

6.0

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.30

Sift

Uncertain

0.013

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.64

MVP

0.64

MPC

0.95

ClinPred

0.020

GERP RS

5.4

Varity_R

0.59

gMVP

0.39

Mutation Taster

=72/28

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over