16-25164665-C-G

Variant names:

• chr16-25164665-C-G
• NM_016309.3:c.637C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016309.3(LCMT1):​c.637C>G​(p.Leu213Val) 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. 15/22 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)
• Consequence: LCMT1 NM_016309.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.612
• Publications: 0 publications found

Genes affected

LCMT1 (HGNC:17557): (leucine carboxyl methyltransferase 1) LCMT1 catalyzes the methylation of the carboxyl group of the C-terminal leucine residue (leu309) of the catalytic subunit of protein phosphatase-2A (PPP2CA; MIM 176915) (De Baere et al., 1999 [PubMed 10600115]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14899614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCMT1	NM_016309.3	c.637C>G	p.Leu213Val	missense_variant	Exon 7 of 11	ENST00000399069.8	NP_057393.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCMT1	ENST00000399069.8	c.637C>G	p.Leu213Val	missense_variant	Exon 7 of 11	1	NM_016309.3	ENSP00000382021.3
LCMT1	ENST00000380962.9	n.*494C>G		non_coding_transcript_exon_variant	Exon 8 of 12	2		ENSP00000370349.5
LCMT1	ENST00000380962.9	n.*494C>G		3_prime_UTR_variant	Exon 8 of 12	2		ENSP00000370349.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.637C>G (p.L213V) alteration is located in exon 7 (coding exon 7) of the LCMT1 gene. This alteration results from a C to G substitution at nucleotide position 637, causing the leucine (L) at amino acid position 213 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.051	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.055	N;.
PhyloP100		-0.61
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.11
Sift	Benign	0.12	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.049	B;B
Vest4		0.38
MutPred		0.68		Loss of catalytic residue at L213 (P = 0.0285);.;
MVP		0.14
MPC		0.32
ClinPred		0.14	T
GERP RS		-0.65
PromoterAI		0.024	Neutral
Varity_R		0.28
gMVP		0.35

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

Other links and lift over

hg19: chr16-25175986;