16-25132483-A-G

Variant names:

• chr16-25132483-A-G
• rs565452933
• NM_016309.3:c.287A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016309.3(LCMT1):​c.287A>G​(p.Asn96Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: LCMT1 NM_016309.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.63
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33380985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCMT1	NM_016309.3	c.287A>G	p.Asn96Ser	missense_variant	Exon 3 of 11	ENST00000399069.8	NP_057393.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCMT1	ENST00000399069.8	c.287A>G	p.Asn96Ser	missense_variant	Exon 3 of 11	1	NM_016309.3	ENSP00000382021.3
LCMT1	ENST00000380962.9	n.*144A>G		non_coding_transcript_exon_variant	Exon 4 of 12	2		ENSP00000370349.5
LCMT1	ENST00000380962.9	n.*144A>G		3_prime_UTR_variant	Exon 4 of 12	2		ENSP00000370349.5

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249218 AF XY: 0.0000518

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461662 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19 AN XY: 727110

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111840

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152298 Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7 AN XY: 74474

African (AFR) AF: 0.0000963 AC: 4 AN: 41552

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000662 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.287A>G (p.N96S) alteration is located in exon 3 (coding exon 3) of the LCMT1 gene. This alteration results from a A to G substitution at nucleotide position 287, causing the asparagine (N) at amino acid position 96 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N;N;.
PhyloP100		8.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;D;.
REVEL	Benign	0.22
Sift	Benign	0.21	T;T;.
Sift4G	Benign	0.41	T;T;T
Polyphen		0.92	P;P;.
Vest4		0.90
MVP		0.59
MPC		0.61
ClinPred		0.51	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.62
Mutation Taster		=44/56	disease causing

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

dbSNP: rs565452933; hg19: chr16-25143804;