15-66548586-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_207338.4(LCTL):​c.1608G>A​(p.Met536Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,454,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LCTL
NM_207338.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08
Variant links:
Genes affected
LCTL (HGNC:15583): (lactase like) This gene encodes a member of family 1 glycosidases. Glycosidases are enzymes that hydrolyze glycosidic bonds and are classified into families based on primary amino acid sequence. Most members of family 1 have two conserved glutamic acid residues, which are required for enzymatic activity. The mouse ortholog of this protein has been characterized and has a domain structure of an N-terminal signal peptide, glycosidase domain, transmembrane domain, and a short cytoplasmic tail. It lacks one of the conserved glutamic acid residues important for catalysis, and its function remains to be determined (PMID: 12084582). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]
ZWILCH (HGNC:25468): (zwilch kinetochore protein) Involved in protein localization to kinetochore. Located in kinetochore. Part of RZZ complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35130882).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LCTLNM_207338.4 linkc.1608G>A p.Met536Ile missense_variant Exon 14 of 14 ENST00000695545.1 NP_997221.2 Q6UWM7-1
ZWILCHNM_017975.5 linkc.*262C>T 3_prime_UTR_variant Exon 19 of 19 ENST00000307897.10 NP_060445.3 Q9H900-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LCTLENST00000695545.1 linkc.1608G>A p.Met536Ile missense_variant Exon 14 of 14 NM_207338.4 ENSP00000512002.1 Q6UWM7-1
ZWILCHENST00000307897.10 linkc.*262C>T 3_prime_UTR_variant Exon 19 of 19 1 NM_017975.5 ENSP00000311429.5 Q9H900-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1454752
Hom.:
0
Cov.:
27
AF XY:
0.00000138
AC XY:
1
AN XY:
724182
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.04e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 25, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1608G>A (p.M536I) alteration is located in exon 13 (coding exon 13) of the LCTL gene. This alteration results from a G to A substitution at nucleotide position 1608, causing the methionine (M) at amino acid position 536 to be replaced by an isoleucine (I). 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
Benign
0.34
BayesDel_addAF
Benign
-0.089
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
23
DANN
Benign
0.82
DEOGEN2
Benign
0.041
T;.
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.032
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.35
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.4
M;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.70
N;N
REVEL
Benign
0.12
Sift
Benign
0.050
D;T
Sift4G
Benign
0.33
T;T
Polyphen
0.0060
B;.
Vest4
0.56
MutPred
0.31
Loss of loop (P = 0.0804);.;
MVP
0.29
MPC
0.31
ClinPred
0.56
D
GERP RS
4.7
Varity_R
0.27
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr15-66840924; API