chr10-27165182-A-T

Variant names:

• chr10-27165182-A-T
• rs7068375
• NM_001172303.3:c.660+12A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001172303.3(MASTL):​c.660+12A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,577,492 control chromosomes in the GnomAD database, including 309,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27731 hom., cov: 30)
  • Exomes 𝑓: 0.62 (281610 hom.)
• Consequence: MASTL NM_001172303.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.21
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• autosomal thrombocytopenia with normal platelets

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-27165182-A-T is Benign according to our data. Variant chr10-27165182-A-T is described in ClinVar as Benign. ClinVar VariationId is 262126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASTL	NM_001172303.3	c.660+12A>T		intron_variant	Intron 5 of 11	ENST00000375940.9	NP_001165774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASTL	ENST00000375940.9	c.660+12A>T		intron_variant	Intron 5 of 11	1	NM_001172303.3	ENSP00000365107.5
MASTL	ENST00000375946.8	c.660+12A>T		intron_variant	Intron 5 of 11	1		ENSP00000365113.4
MASTL	ENST00000342386.10	c.660+12A>T		intron_variant	Intron 5 of 10	2		ENSP00000343446.5

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91263 AN: 151778 Hom.: 27737 Cov.: 30

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.591 AC: 148154 AN: 250732 AF XY: 0.590

Gnomad AFR exome AF: 0.549

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.434

Gnomad FIN exome AF: 0.663

Gnomad NFE exome AF: 0.650

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.625 AC: 890655 AN: 1425596 Hom.: 281610 Cov.: 26 AF XY: 0.621 AC XY: 442201 AN XY: 711538

African (AFR) AF: 0.554 AC: 18093 AN: 32664

American (AMR) AF: 0.537 AC: 24000 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 16021 AN: 25900

East Asian (EAS) AF: 0.398 AC: 15707 AN: 39468

South Asian (SAS) AF: 0.492 AC: 42024 AN: 85450

European-Finnish (FIN) AF: 0.661 AC: 35264 AN: 53350

Middle Eastern (MID) AF: 0.579 AC: 3293 AN: 5690

European-Non Finnish (NFE) AF: 0.649 AC: 700070 AN: 1079212

Other (OTH) AF: 0.611 AC: 36183 AN: 59196

GnomAD4 genome AF: 0.601 AC: 91267 AN: 151896 Hom.: 27731 Cov.: 30 AF XY: 0.600 AC XY: 44502 AN XY: 74210

African (AFR) AF: 0.553 AC: 22887 AN: 41410

American (AMR) AF: 0.570 AC: 8703 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2180 AN: 3466

East Asian (EAS) AF: 0.425 AC: 2188 AN: 5148

South Asian (SAS) AF: 0.479 AC: 2305 AN: 4814

European-Finnish (FIN) AF: 0.662 AC: 6962 AN: 10518

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44067 AN: 67946

Other (OTH) AF: 0.585 AC: 1236 AN: 2112

Alfa AF: 0.627 Hom.: 5573

Bravo AF: 0.593

Asia WGS AF: 0.443 AC: 1542 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocytopenia Benign:1

Jan 13, 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
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.0
DANN	Benign	0.67
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7068375; hg19: chr10-27454111; COSMIC: COSV60909955; COSMIC: COSV60909955;