19-18122750-C-T

Variant names:

• chr19-18122750-C-T
• NM_001393504.1:c.398C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001393504.1(MAST3):​c.398C>T​(p.Ser133Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAST3 NM_001393504.1 missense, splice_region
• Scores: Splicing: ADA: 0.9897
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.43
• Publications: 1 publications found

Genes affected

MAST3 (HGNC:19036): (microtubule associated serine/threonine kinase 3) Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in cytoskeleton organization; intracellular signal transduction; and peptidyl-serine phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

MAST3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 108

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000297168 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 19-18122750-C-T is Pathogenic according to our data. Variant chr19-18122750-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3342723.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393504.1. 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
	MAST3	NM_001393504.1	MANE Select	c.398C>T	p.Ser133Leu	missense splice_region	Exon 6 of 28	NP_001380433.1	A0A8I5KST9
	MAST3	NM_001393501.1		c.422C>T	p.Ser141Leu	missense splice_region	Exon 7 of 29	NP_001380430.1
	MAST3	NM_001393502.1		c.401C>T	p.Ser134Leu	missense splice_region	Exon 6 of 28	NP_001380431.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAST3	ENST00000687212.1	MANE Select	c.398C>T	p.Ser133Leu	missense splice_region	Exon 6 of 28	ENSP00000509890.1	A0A8I5KST9
	MAST3	ENST00000262811.10	TSL:1	c.311C>T	p.Ser104Leu	missense splice_region	Exon 5 of 27	ENSP00000262811.4	O60307
	MAST3	ENST00000893417.1		c.311C>T	p.Ser104Leu	missense	Exon 5 of 27	ENSP00000563476.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.59
MutPred		0.57		Loss of phosphorylation at S104 (P = 0.0048)
MVP		0.60
MPC		0.94
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.68
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 1

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

Other links and lift over

hg19: chr19-18233560; COSMIC: COSV53217754; COSMIC: COSV53217754;