rs36121140

Variant names:

• chr10-27169969-C-A
• rs36121140
• NM_001172303.3:c.1010C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-27169969-C-A
• chr10-27169969-C-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.1010C>A​(p.Thr337Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,614,016 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (264 hom.)
• Consequence: MASTL NM_001172303.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.108
• Publications: 9 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]

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]

ACBD5 Gene-Disease associations (from GenCC):

• retinal dystrophy with leukodystrophy

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• acyl-CoA binding domain containing protein 5 deficiency

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025212765).
• BP6: Variant 10-27169969-C-A is Benign according to our data. Variant chr10-27169969-C-A is described in ClinVar as Benign. ClinVar VariationId is 262114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASTL	NM_001172303.3	c.1010C>A	p.Thr337Lys	missense_variant	Exon 8 of 12	ENST00000375940.9	NP_001165774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASTL	ENST00000375940.9	c.1010C>A	p.Thr337Lys	missense_variant	Exon 8 of 12	1	NM_001172303.3	ENSP00000365107.5

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 873 AN: 152078 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0117 AC: 2940 AN: 250774 AF XY: 0.0119

Gnomad AFR exome AF: 0.000925

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00638

GnomAD4 exome AF: 0.00555 AC: 8115 AN: 1461820 Hom.: 264 Cov.: 33 AF XY: 0.00598 AC XY: 4351 AN XY: 727208

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26134

East Asian (EAS) AF: 0.100 AC: 3986 AN: 39688

South Asian (SAS) AF: 0.0186 AC: 1605 AN: 86252

European-Finnish (FIN) AF: 0.00225 AC: 120 AN: 53384

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00154 AC: 1713 AN: 1111996

Other (OTH) AF: 0.00934 AC: 564 AN: 60396

GnomAD4 genome AF: 0.00574 AC: 873 AN: 152196 Hom.: 38 Cov.: 33 AF XY: 0.00660 AC XY: 491 AN XY: 74400

African (AFR) AF: 0.000626 AC: 26 AN: 41516

American (AMR) AF: 0.00177 AC: 27 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.110 AC: 570 AN: 5174

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4822

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68028

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00572 Hom.: 59

Bravo AF: 0.00624

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.0117 AC: 1416

Asia WGS AF: 0.0420 AC: 146 AN: 3476

EpiCase AF: 0.00169

EpiControl AF: 0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.3
DANN	Benign	0.37
DEOGEN2	Benign	0.014	.;T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.60	T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;.
PhyloP100		-0.11
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;N;.
REVEL	Benign	0.033
Sift	Benign	0.060	T;T;T;.
Sift4G	Benign	0.88	T;T;T;T
Polyphen		0.0030	B;B;B;.
Vest4		0.034
MPC		0.13
ClinPred		0.0020	T
GERP RS		0.79
PromoterAI		-0.018	Neutral
Varity_R		0.034
gMVP		0.33
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs36121140; hg19: chr10-27458898; COSMIC: COSV60911150;