rs3802526

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001172303.3(MASTL):c.1858C>G(p.Pro620Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0652 in 1,613,964 control chromosomes in the GnomAD database, including 4,616 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.073 ( 474 hom., cov: 32)

Exomes 𝑓: 0.064 ( 4142 hom. )

Consequence

MASTL
NM_001172303.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.331

Variant links:

Genes affected

MASTL (HGNC:19042): (microtubule associated serine/threonine kinase like) This gene encodes a microtubule-associated serine/threonine kinase. Mutations at this locus have been associated with autosomal dominant thrombocytopenia, also known as thrombocytopenia-2. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Feb 2010]

MASTL links:

ACBD5 (HGNC:23338): (acyl-CoA binding domain containing 5) This gene encodes a member of the acyl-Coenzyme A binding protein family, known to function in the transport and distribution of long chain acyl-Coenzyme A in cells. This gene may play a role in the differentiation of megakaryocytes and formation of platelets. A related protein in yeast is involved in autophagy of peroxisomes. A mutation in this gene has been associated with autosomal dominant thrombocytopenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACBD5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017546713).

BP6

Variant 10-27170817-C-G is Benign according to our data. Variant chr10-27170817-C-G is described in ClinVar as [Benign]. Clinvar id is 262116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASTL	NM_001172303.3 link	c.1858C>G	p.Pro620Ala	missense_variant	8/12	ENST00000375940.9	NP_001165774.1	Q96GX5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASTL	ENST00000375940.9 link	c.1858C>G	p.Pro620Ala	missense_variant	8/12	1	NM_001172303.3	ENSP00000365107.5		Q96GX5-1

Frequencies

GnomAD3 genomes

AF:

0.0730

AC:

11108

AN:

152078

Hom.:

474

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0848

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0508

Gnomad ASJ

AF:

0.0773

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0541

Gnomad OTH

AF:

0.0531

GnomAD3 exomes

AF:

0.0821

AC:

20620

AN:

251038

Hom.:

1083

AF XY:

0.0842

AC XY:

11423

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.0854

Gnomad AMR exome

AF:

0.0657

Gnomad ASJ exome

AF:

0.0729

Gnomad EAS exome

AF:

0.149

Gnomad SAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.0548

Gnomad OTH exome

AF:

0.0675

GnomAD4 exome

AF:

0.0644

AC:

94112

AN:

1461768

Hom.:

4142

Cov.:

AF XY:

0.0667

AC XY:

48502

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0869

Gnomad4 AMR exome

AF:

0.0623

Gnomad4 ASJ exome

AF:

0.0735

Gnomad4 EAS exome

AF:

0.206

Gnomad4 SAS exome

AF:

0.144

Gnomad4 FIN exome

AF:

0.109

Gnomad4 NFE exome

AF:

0.0502

Gnomad4 OTH exome

AF:

0.0669

GnomAD4 genome

AF:

0.0731

AC:

11124

AN:

152196

Hom.:

474

Cov.:

AF XY:

0.0772

AC XY:

5744

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0852

Gnomad4 AMR

AF:

0.0507

Gnomad4 ASJ

AF:

0.0773

Gnomad4 EAS

AF:

0.160

Gnomad4 SAS

AF:

0.156

Gnomad4 FIN

AF:

0.108

Gnomad4 NFE

AF:

0.0541

Gnomad4 OTH

AF:

0.0530

Alfa

AF:

0.0597

Hom.:

279

Bravo

AF:

0.0689

TwinsUK

AF:

0.0539

AC:

200

ALSPAC

AF:

0.0485

AC:

187

ESP6500AA

AF:

0.0819

AC:

361

ESP6500EA

AF:

0.0522

AC:

449

ExAC

AF:

0.0840

AC:

10204

Asia WGS

AF:

0.154

AC:

533

AN:

3478

EpiCase

AF:

0.0528

EpiControl

AF:

0.0499

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Thrombocytopenia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

5.1

DANN

Benign

0.75

DEOGEN2

Benign

0.013

.;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.77

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

N;N;N;.

REVEL

Benign

0.063

Sift

Benign

0.18

T;T;T;.

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.29

B;B;B;.

Vest4

0.16

MPC

0.15

ClinPred

0.017

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over