15-66548586-C-T

Variant names:

• chr15-66548586-C-T
• NM_207338.4:c.1608G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08

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]

ACMG classification

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
LCTL	NM_207338.4	c.1608G>A	p.Met536Ile	missense_variant	Exon 14 of 14	ENST00000695545.1	NP_997221.2
ZWILCH	NM_017975.5	c.*262C>T		3_prime_UTR_variant	Exon 19 of 19	ENST00000307897.10	NP_060445.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCTL	ENST00000695545.1	c.1608G>A	p.Met536Ile	missense_variant	Exon 14 of 14		NM_207338.4	ENSP00000512002.1
ZWILCH	ENST00000307897.10	c.*262C>T		3_prime_UTR_variant	Exon 19 of 19	1	NM_017975.5	ENSP00000311429.5

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

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

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;