NM_001172303.3:c.-28C>A

Variant names:

• chr10-27155399-C-A
• rs7919803
• NM_001172303.3:c.-28C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001172303.3(MASTL):​c.-28C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 1,575,846 control chromosomes in the GnomAD database, including 309,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27801 hom., cov: 32)
  • Exomes 𝑓: 0.63 (282083 hom.)
• Consequence: MASTL NM_001172303.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.224

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 10-27155399-C-A is Benign according to our data. Variant chr10-27155399-C-A is described in ClinVar as [Benign]. Clinvar id is 262113.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.-28C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	ENST00000375940.9	NP_001165774.1
MASTL	NM_001172303.3	c.-28C>A		5_prime_UTR_variant	Exon 1 of 12	ENST00000375940.9	NP_001165774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASTL	ENST00000375940	c.-28C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	1	NM_001172303.3	ENSP00000365107.5
MASTL	ENST00000375940	c.-28C>A		5_prime_UTR_variant	Exon 1 of 12	1	NM_001172303.3	ENSP00000365107.5

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91400 AN: 151786 Hom.: 27804 Cov.: 32

Gnomad AFR AF: 0.557

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: 0.583

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.592

GnomAD3 exomes AF: 0.592 AC: 115272 AN: 194594 Hom.: 34644 AF XY: 0.590 AC XY: 62832 AN XY: 106548

Gnomad AFR exome AF: 0.554

Gnomad AMR exome AF: 0.541

Gnomad ASJ exome AF: 0.616

Gnomad EAS exome AF: 0.441

Gnomad SAS exome AF: 0.488

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.653

Gnomad OTH exome AF: 0.625

GnomAD4 exome AF: 0.626 AC: 891481 AN: 1423946 Hom.: 282083 Cov.: 33 AF XY: 0.623 AC XY: 439517 AN XY: 705682

Gnomad4 AFR exome AF: 0.559

Gnomad4 AMR exome AF: 0.541

Gnomad4 ASJ exome AF: 0.620

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.663

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.612

GnomAD4 genome AF: 0.602 AC: 91406 AN: 151900 Hom.: 27801 Cov.: 32 AF XY: 0.601 AC XY: 44600 AN XY: 74238

Gnomad4 AFR AF: 0.556

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.662

Gnomad4 NFE AF: 0.648

Gnomad4 OTH AF: 0.585

Alfa AF: 0.628 Hom.: 5507

Bravo AF: 0.594

Asia WGS AF: 0.445 AC: 1549 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.74
CADD	Benign	8.0
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs7919803; hg19: chr10-27444328; COSMIC: COSV58759031; COSMIC: COSV58759031;