rs1981296

Positions:

• chr10-27170741-C-T

Variant summary

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

The ENST00000375940.9(MASTL):​c.1782C>T​(p.Ile594=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,613,170 control chromosomes in the GnomAD database, including 315,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27755 hom., cov: 32)
  • Exomes 𝑓: 0.62 (288127 hom.)
• Consequence: MASTL ENST00000375940.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.229

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-27170741-C-T is Benign according to our data. Variant chr10-27170741-C-T is described in ClinVar as [Benign]. Clinvar id is 262115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-27170741-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.229 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASTL	NM_001172303.3	c.1782C>T	p.Ile594=	synonymous_variant	8/12	ENST00000375940.9	NP_001165774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASTL	ENST00000375940.9	c.1782C>T	p.Ile594=	synonymous_variant	8/12	1	NM_001172303.3	ENSP00000365107	P5

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91331 AN: 151866 Hom.: 27761 Cov.: 32

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.595

GnomAD3 exomes AF: 0.590 AC: 147703 AN: 250204 Hom.: 44387 AF XY: 0.590 AC XY: 79898 AN XY: 135424

Gnomad AFR exome AF: 0.547

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.433

Gnomad SAS exome AF: 0.486

Gnomad FIN exome AF: 0.663

Gnomad NFE exome AF: 0.649

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.624 AC: 912404 AN: 1461186 Hom.: 288127 Cov.: 42 AF XY: 0.621 AC XY: 451642 AN XY: 726908

Gnomad4 AFR exome AF: 0.554

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.619

Gnomad4 EAS exome AF: 0.398

Gnomad4 SAS exome AF: 0.491

Gnomad4 FIN exome AF: 0.661

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.610

GnomAD4 genome AF: 0.601 AC: 91335 AN: 151984 Hom.: 27755 Cov.: 32 AF XY: 0.600 AC XY: 44549 AN XY: 74292

Gnomad4 AFR AF: 0.553

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.478

Gnomad4 FIN AF: 0.662

Gnomad4 NFE AF: 0.649

Gnomad4 OTH AF: 0.587

Alfa AF: 0.637 Hom.: 54822

Bravo AF: 0.593

Asia WGS AF: 0.444 AC: 1546 AN: 3478

EpiCase AF: 0.644

EpiControl AF: 0.640

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
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
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.5
DANN	Benign	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: rs1981296; hg19: chr10-27459670; COSMIC: COSV60909840;