18-8718599-C-A

Position:

• chr18-8718599-C-A

Variant summary

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

The NM_001395333.1(MTCL1):​c.1229C>A​(p.Thr410Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTCL1 NM_001395333.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06

Genes affected

MTCL1 (HGNC:29121): (microtubule crosslinking factor 1) Enables microtubule binding activity. Predicted to be involved in establishment or maintenance of epithelial cell apical/basal polarity; microtubule bundle formation; and positive regulation of protein targeting to membrane. Located in midbody and spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

MTCL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTCL1	NM_001395333.1	c.1229C>A	p.Thr410Lys	missense_variant	2/15	ENST00000695636.1	NP_001382262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTCL1	ENST00000695636.1	c.1229C>A	p.Thr410Lys	missense_variant	2/15		NM_001395333.1	ENSP00000512073.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2024

The c.149C>A (p.T50K) alteration is located in exon 3 (coding exon 1) of the MTCL1 gene. This alteration results from a C to A substitution at nucleotide position 149, causing the threonine (T) at amino acid position 50 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Uncertain	0.079	D
MutationAssessor	Uncertain	2.5	M;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	.;D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.022	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.65
MutPred		0.29		.;Gain of ubiquitination at T50 (P = 0.0075);Gain of ubiquitination at T50 (P = 0.0075);Gain of ubiquitination at T50 (P = 0.0075);
MVP		0.56
MPC		0.50
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.094
gMVP		0.73

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: chr18-8718597;