chr10-27155400-T-C

Variant names:

• chr10-27155400-T-C
• rs7907981
• NM_001172303.3:c.-27T>C

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.-27T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.785 in 1,577,752 control chromosomes in the GnomAD database, including 487,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47979 hom., cov: 32)
  • Exomes 𝑓: 0.78 (439592 hom.)
• Consequence: MASTL NM_001172303.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.35
• Publications: 10 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]

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]

YME1L1 Gene-Disease associations (from GenCC):

• autosomal recessive optic atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• optic atrophy 11

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-27155400-T-C is Benign according to our data. Variant chr10-27155400-T-C is described in ClinVar as Benign. ClinVar VariationId is 262112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASTL	NM_001172303.3	c.-27T>C		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	ENST00000375940.9	c.-27T>C		5_prime_UTR_variant	Exon 1 of 12	1	NM_001172303.3	ENSP00000365107.5
MASTL	ENST00000375946.8	c.-27T>C		5_prime_UTR_variant	Exon 1 of 12	1		ENSP00000365113.4
MASTL	ENST00000342386.10	c.-27T>C		5_prime_UTR_variant	Exon 1 of 11	2		ENSP00000343446.5
YME1L1	ENST00000477432.1	c.-1190A>G		upstream_gene_variant		1		ENSP00000473302.1

Frequencies

GnomAD3 genomes AF: 0.793 AC: 120390 AN: 151830 Hom.: 47953 Cov.: 32

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.778

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.736

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.779

GnomAD2 exomes AF: 0.799 AC: 157070 AN: 196508 AF XY: 0.800

Gnomad AFR exome AF: 0.790

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.988

Gnomad FIN exome AF: 0.879

Gnomad NFE exome AF: 0.775

Gnomad OTH exome AF: 0.793

GnomAD4 exome AF: 0.784 AC: 1117627 AN: 1425804 Hom.: 439592 Cov.: 35 AF XY: 0.785 AC XY: 554701 AN XY: 706760

African (AFR) AF: 0.793 AC: 25792 AN: 32508

American (AMR) AF: 0.717 AC: 27839 AN: 38812

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 19865 AN: 25528

East Asian (EAS) AF: 0.983 AC: 37101 AN: 37748

South Asian (SAS) AF: 0.819 AC: 68450 AN: 83544

European-Finnish (FIN) AF: 0.871 AC: 42684 AN: 49022

Middle Eastern (MID) AF: 0.765 AC: 3177 AN: 4154

European-Non Finnish (NFE) AF: 0.772 AC: 846161 AN: 1095516

Other (OTH) AF: 0.789 AC: 46558 AN: 58972

GnomAD4 genome AF: 0.793 AC: 120466 AN: 151948 Hom.: 47979 Cov.: 32 AF XY: 0.801 AC XY: 59519 AN XY: 74276

African (AFR) AF: 0.797 AC: 33068 AN: 41470

American (AMR) AF: 0.740 AC: 11310 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 2696 AN: 3466

East Asian (EAS) AF: 0.987 AC: 5058 AN: 5126

South Asian (SAS) AF: 0.833 AC: 4017 AN: 4822

European-Finnish (FIN) AF: 0.879 AC: 9312 AN: 10588

Middle Eastern (MID) AF: 0.740 AC: 216 AN: 292

European-Non Finnish (NFE) AF: 0.772 AC: 52436 AN: 67884

Other (OTH) AF: 0.781 AC: 1647 AN: 2108

Alfa AF: 0.741 Hom.: 4629

Bravo AF: 0.781

Asia WGS AF: 0.884 AC: 3073 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	-0.81
CADD	Benign	0.47
DANN	Benign	0.48
PhyloP100		-4.3
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs7907981; hg19: chr10-27444329;