19-12838595-C-T

Variant names:

• chr19-12838595-C-T
• NM_014975.3:c.23C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014975.3(MAST1):​c.23C>T​(p.Ala8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MAST1 NM_014975.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.719

Genes affected

MAST1 (HGNC:19034): (microtubule associated serine/threonine kinase 1) This gene is a member of the microtubule-associated serine/threonine kinase (MAST) family. The protein encoded by this gene has an N-terminal serine/threonine kinase domain followed by a postsynaptic density protein-95/discs large/zona occludens-1 (PDZ) domain. In mouse and rat, the orthologous protein associates with the cytoskeleton and can bind both beta-2-syntrophin and neuronal nitric oxide synthase (nNOS) through its PDZ domain. In mouse and rat, this protein also co-localizes with dystrophin- and utrophin-associated protein complexes (DAPC/UAPC) in the vascular endothelium of the central nervous system. [provided by RefSeq, May 2017]

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17697129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAST1	NM_014975.3	c.23C>T	p.Ala8Val	missense_variant	Exon 1 of 26	ENST00000251472.9	NP_055790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAST1	ENST00000251472.9	c.23C>T	p.Ala8Val	missense_variant	Exon 1 of 26	1	NM_014975.3	ENSP00000251472.3
MAST1	ENST00000591495.6	c.71+295C>T		intron_variant	Intron 2 of 12	5		ENSP00000466470.1
MAST1	ENST00000590883.1	n.123C>T		non_coding_transcript_exon_variant	Exon 1 of 6	5
HOOK2	ENST00000589765.1	n.33-12095G>A		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 8 of the MAST1 protein (p.Ala8Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MAST1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.97	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.070
Sift	Benign	0.16	T
Sift4G	Benign	0.42	T
Polyphen		0.013	B
Vest4		0.14
MutPred		0.18		Loss of helix (P = 0.028);
MVP		0.52
ClinPred		0.53	D
GERP RS		2.9
Varity_R		0.13
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-12949409;