rs56204835

Variant names:

• chr10-27161106-G-A
• rs56204835
• NM_001172303.3:c.477G>A
• MASTL p.Pro159Pro

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001172303.3(MASTL):​c.477G>A​(p.Pro159Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,611,822 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00062 (8 hom.)
• Consequence: MASTL NM_001172303.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.11
• Publications: 2 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
• thrombocytopenia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 10-27161106-G-A is Benign according to our data. Variant chr10-27161106-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00542 (824/152096) while in subpopulation AFR AF = 0.0188 (778/41458). AF 95% confidence interval is 0.0177. There are 10 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 824 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASTL	NM_001172303.3	MANE Select	c.477G>A	p.Pro159Pro	synonymous	Exon 4 of 12	NP_001165774.1	Q96GX5-1
	MASTL	NM_001320757.2		c.477G>A	p.Pro159Pro	synonymous	Exon 4 of 13	NP_001307686.1
	MASTL	NM_001320756.2		c.477G>A	p.Pro159Pro	synonymous	Exon 4 of 13	NP_001307685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASTL	ENST00000375940.9	TSL:1 MANE Select	c.477G>A	p.Pro159Pro	synonymous	Exon 4 of 12	ENSP00000365107.5	Q96GX5-1
	MASTL	ENST00000375946.8	TSL:1	c.477G>A	p.Pro159Pro	synonymous	Exon 4 of 12	ENSP00000365113.4	Q96GX5-3
	MASTL	ENST00000969651.1		c.477G>A	p.Pro159Pro	synonymous	Exon 4 of 13	ENSP00000639710.1

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 822 AN: 151976 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00150 AC: 376 AN: 251464 AF XY: 0.00110

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000615 AC: 898 AN: 1459726 Hom.: 8 Cov.: 29 AF XY: 0.000505 AC XY: 367 AN XY: 726360

African (AFR) AF: 0.0194 AC: 649 AN: 33414

American (AMR) AF: 0.000716 AC: 32 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.0000631 AC: 70 AN: 1110126

Other (OTH) AF: 0.00131 AC: 79 AN: 60320

GnomAD4 genome AF: 0.00542 AC: 824 AN: 152096 Hom.: 10 Cov.: 31 AF XY: 0.00534 AC XY: 397 AN XY: 74342

African (AFR) AF: 0.0188 AC: 778 AN: 41458

American (AMR) AF: 0.00196 AC: 30 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68000

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00273 Hom.: 0

Bravo AF: 0.00623

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Thrombocytopenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56204835;

hg19: chr10-27450035;

COSMIC: COSV100669015;