10-27170373-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001172303.3(MASTL):c.1414G>A(p.Glu472Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,762 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E472G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (3 hom.)
• Consequence: MASTL NM_001172303.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.499

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010948092).
• BS2: High AC in GnomAd at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MASTL	NM_001172303.3	c.1414G>A	p.Glu472Lys	missense_variant	8/12	ENST00000375940.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MASTL	ENST00000375940.9	c.1414G>A	p.Glu472Lys	missense_variant	8/12	1	NM_001172303.3	P5

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 250698 Hom.: 1 AF XY: 0.000369 AC XY: 50 AN XY: 135600

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1461514 Hom.: 3 Cov.: 33 AF XY: 0.000204 AC XY: 148 AN XY: 727086

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74434

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000617 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MASTL-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2023

The MASTL c.1414G>A variant is predicted to result in the amino acid substitution p.Glu472Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of South Asian descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/10-27459302-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	16
Dann	Benign	0.74
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.39	N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.38	T;T;T;.
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.040	B;B;B;.
Vest4		0.11
MVP		0.16
MPC		0.13
ClinPred		0.013	T
GERP RS		2.4
Varity_R		0.038
gMVP		0.18

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: rs200461088; hg19: chr10-27459302; COSMIC: COSV60909557;