rs151176548

chr10-27155460-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.69

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MASTL	NM_001172303.3	c.34G>C	p.Gly12Arg	missense_variant	1/12	ENST00000375940.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MASTL	ENST00000375940.9	c.34G>C	p.Gly12Arg	missense_variant	1/12	1	NM_001172303.3	P5
MASTL	ENST00000375946.8	c.34G>C	p.Gly12Arg	missense_variant	1/12	1		A1
MASTL	ENST00000342386.10	c.34G>C	p.Gly12Arg	missense_variant	1/11	2

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152254 Hom.: 3 Cov.: 33

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

GnomAD3 exomes AF: 0.00322 AC: 802 AN: 249052 Hom.: 9 AF XY: 0.00407 AC XY: 550 AN XY: 134988

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 SAS exome AF: 0.0196

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.: 41 Cov.: 34 AF XY: 0.00252 AC XY: 1831 AN XY: 726772

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.000750

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152372 Hom.: 3 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74518

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.000865

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00348 AC: 422

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2018

- -

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	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
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	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.066
gMVP		0.62

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

Other links and lift over

dbSNP: rs151176548; hg19: chr10-27444389; COSMIC: COSV99045153; COSMIC: COSV99045153;