10-27186515-T-C

Position:

• chr10-27186515-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001172303.3(MASTL):​c.2619T>C​(p.Thr873Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,612,818 control chromosomes in the GnomAD database, including 323,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28393 hom., cov: 32)
  • Exomes 𝑓: 0.63 (294887 hom.)
• Consequence: MASTL NM_001172303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.27

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]

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]

MASTL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-27186515-T-C is Benign according to our data. Variant chr10-27186515-T-C is described in ClinVar as [Benign]. Clinvar id is 262122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-27186515-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASTL	NM_001172303.3	c.2619T>C	p.Thr873Thr	synonymous_variant	12/12	ENST00000375940.9	NP_001165774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASTL	ENST00000375940.9	c.2619T>C	p.Thr873Thr	synonymous_variant	12/12	1	NM_001172303.3	ENSP00000365107.5

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92341 AN: 151806 Hom.: 28395 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.669

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.596

GnomAD3 exomes AF: 0.596 AC: 149846 AN: 251410 Hom.: 45528 AF XY: 0.595 AC XY: 80896 AN XY: 135866

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.436

Gnomad SAS exome AF: 0.485

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.658

Gnomad OTH exome AF: 0.620

GnomAD4 exome AF: 0.632 AC: 923262 AN: 1460894 Hom.: 294887 Cov.: 48 AF XY: 0.629 AC XY: 456836 AN XY: 726812

Gnomad4 AFR exome AF: 0.564

Gnomad4 AMR exome AF: 0.538

Gnomad4 ASJ exome AF: 0.619

Gnomad4 EAS exome AF: 0.429

Gnomad4 SAS exome AF: 0.491

Gnomad4 FIN exome AF: 0.670

Gnomad4 NFE exome AF: 0.656

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.608 AC: 92350 AN: 151924 Hom.: 28393 Cov.: 32 AF XY: 0.607 AC XY: 45029 AN XY: 74244

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.571

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.477

Gnomad4 FIN AF: 0.669

Gnomad4 NFE AF: 0.655

Gnomad4 OTH AF: 0.589

Alfa AF: 0.631 Hom.: 15995

Bravo AF: 0.600

Asia WGS AF: 0.448 AC: 1558 AN: 3478

EpiCase AF: 0.650

EpiControl AF: 0.646

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Thrombocytopenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.38
DANN	Benign	0.50

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: rs10741130; hg19: chr10-27475444; COSMIC: COSV60909974;