rs151176548

Variant names:

Variant summary

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

The NM_001172303.3(MASTL):c.34G>C(p.Gly12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,378 control chromosomes in the GnomAD database, including 44 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 41 hom. )

Consequence

MASTL
NM_001172303.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.69

Publications

3 publications found

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:

YME1L1 (HGNC:12843): (YME1 like 1 ATPase) The protein encoded by this gene is the human ortholog of yeast mitochondrial AAA metalloprotease, Yme1p. It is localized in the mitochondria and can functionally complement a yme1 disruptant yeast strain. It is proposed that this gene plays a role in mitochondrial protein metabolism and could be involved in mitochondrial pathologies. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

YME1L1 Gene-Disease associations (from GenCC):

autosomal recessive optic atrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
optic atrophy 11
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

YME1L1 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=0.0043290854).

BP6

Variant 10-27155460-G-C is Benign according to our data. Variant chr10-27155460-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00144 (219/152372) while in subpopulation SAS AF = 0.0224 (108/4830). AF 95% confidence interval is 0.0189. There are 3 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASTL	NM_001172303.3 link	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 12	ENST00000375940.9	NP_001165774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MASTL	ENST00000375940.9 link	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 12	1	NM_001172303.3	ENSP00000365107.5
MASTL	ENST00000375946.8 link	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 12	1		ENSP00000365113.4
MASTL	ENST00000342386.10 link	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 11	2		ENSP00000343446.5
YME1L1	ENST00000477432.1 link	c.-1250C>G		upstream_gene_variant		1		ENSP00000473302.1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0223

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00322

AC:

802

AN:

249052

AF XY:

0.00407

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00539

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000932

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00197

AC:

2876

AN:

1461006

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

1831

AN XY:

726772

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33462

American (AMR)

AF:

0.000425

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00555

AC:

145

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39686

South Asian (SAS)

AF:

0.0193

AC:

1663

AN:

86210

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00590

AC:

AN:

5424

European-Non Finnish (NFE)

AF:

0.000750

AC:

834

AN:

1111750

Other (OTH)

AF:

0.00250

AC:

151

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

183

366

548

731

914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00144

AC:

219

AN:

152372

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41592

American (AMR)

AF:

0.000588

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

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:

0.00156

Hom.:

Bravo

AF:

0.000865

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00348

AC:

422

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thrombocytopenia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

.;T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.65

T;T;T

MetaRNN

Benign

0.0043

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

2.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.35

N;N;N

REVEL

Benign

0.074

Sift

Benign

0.077

T;D;D

Sift4G

Benign

0.35

T;T;T

Polyphen

0.058

B;B;P

Vest4

0.10

MutPred

0.23

Gain of ubiquitination at K8 (P = 0.0833);Gain of ubiquitination at K8 (P = 0.0833);Gain of ubiquitination at K8 (P = 0.0833);

MVP

0.38

MPC

0.13

ClinPred

0.028

GERP RS

4.0

PromoterAI

-0.041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.066

gMVP

0.62

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over