Genetic Variant MAST3:p.Thr225Met (chr19-18123979-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001393504.1(MAST3):c.674C>T(p.Thr225Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,584,122 control chromosomes in the GnomAD database, including 495 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 85 hom., cov: 32)

Exomes 𝑓: 0.015 ( 410 hom. )

Consequence

MAST3
NM_001393504.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.25

Publications

6 publications found

Variant links:

Genes affected

MAST3 (HGNC:19036): (microtubule associated serine/threonine kinase 3) Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in cytoskeleton organization; intracellular signal transduction; and peptidyl-serine phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

MAST3 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy 108
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

MAST3 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=0.0024982989).

BP6

Variant 19-18123979-C-T is Benign according to our data. Variant chr19-18123979-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAST3	NM_001393504.1 link	c.674C>T	p.Thr225Met	missense_variant	Exon 9 of 28	ENST00000687212.1	NP_001380433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAST3	ENST00000687212.1 link	c.674C>T	p.Thr225Met	missense_variant	Exon 9 of 28		NM_001393504.1	ENSP00000509890.1		A0A8I5KST9

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2794

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00357

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0740

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.0414

Gnomad SAS

AF:

0.0548

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.0306

AC:

6112

AN:

199496

AF XY:

0.0292

show subpopulations

Gnomad AFR exome

AF:

0.00266

Gnomad AMR exome

AF:

0.0926

Gnomad ASJ exome

AF:

0.0311

Gnomad EAS exome

AF:

0.0383

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.00975

Gnomad OTH exome

AF:

0.0216

GnomAD4 exome

AF:

0.0149

AC:

21319

AN:

1431790

Hom.:

410

Cov.:

AF XY:

0.0158

AC XY:

11209

AN XY:

710282

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

32668

American (AMR)

AF:

0.0904

AC:

3719

AN:

41120

Ashkenazi Jewish (ASJ)

AF:

0.0298

AC:

765

AN:

25648

East Asian (EAS)

AF:

0.0266

AC:

1004

AN:

37806

South Asian (SAS)

AF:

0.0490

AC:

4039

AN:

82364

European-Finnish (FIN)

AF:

0.0115

AC:

544

AN:

47400

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00915

AC:

10057

AN:

1099712

Other (OTH)

AF:

0.0177

AC:

1052

AN:

59328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1492

2984

4477

5969

7461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

454

908

1362

1816

2270

<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:

0.0184

AC:

2805

AN:

152332

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1520

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00356

AC:

148

AN:

41580

American (AMR)

AF:

0.0743

AC:

1137

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

AN:

3470

East Asian (EAS)

AF:

0.0413

AC:

214

AN:

5180

South Asian (SAS)

AF:

0.0551

AC:

266

AN:

4828

European-Finnish (FIN)

AF:

0.0113

AC:

120

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0114

AC:

776

AN:

68030

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

139

278

418

557

696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0136

Hom.:

Bravo

AF:

0.0212

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00403

AC:

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.0228

AC:

2735

Asia WGS

AF:

0.0530

AC:

183

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

1.2

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.068

Sift

Benign

0.076

Sift4G

Benign

0.10

Polyphen

0.51

Vest4

0.052

MPC

1.2

ClinPred

0.029

GERP RS

2.4

Varity_R

0.037

gMVP

0.13

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over