18-8783655-G-T

Variant summary

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

The NM_001395333.1(MTCL1):c.1623G>T(p.Lys541Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTCL1 NM_001395333.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

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]

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	UniProt
MTCL1	NM_001395333.1	c.1623G>T	p.Lys541Asn	missense_variant	5/15	ENST00000695636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTCL1	ENST00000695636.1	c.1623G>T	p.Lys541Asn	missense_variant	5/15		NM_001395333.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Dec 26, 2023

The c.543G>T (p.K181N) alteration is located in exon 6 (coding exon 4) of the MTCL1 gene. This alteration results from a G to T substitution at nucleotide position 543, causing the lysine (K) at amino acid position 181 to be replaced by an asparagine (N). 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	0.96
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	23
Dann	Benign	0.95
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.69
MutPred		0.12		.;Loss of ubiquitination at K181 (P = 0.0047);Loss of ubiquitination at K181 (P = 0.0047);Loss of ubiquitination at K181 (P = 0.0047);
MVP		0.64
MPC		0.52
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.13
gMVP		0.68

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: chr18-8783653;