Genetic Variant LCMT1:p.Arg248Ser (chr16-25169163-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016309.3(LCMT1):c.742C>A(p.Arg248Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R248C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LCMT1
NM_016309.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

Publications

0 publications found

Variant links:

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]

LCMT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCMT1	NM_016309.3 link	c.742C>A	p.Arg248Ser	missense_variant	Exon 8 of 11	ENST00000399069.8	NP_057393.2	Q9UIC8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LCMT1	ENST00000399069.8 link	c.742C>A	p.Arg248Ser	missense_variant	Exon 8 of 11	1	NM_016309.3	ENSP00000382021.3	Q9UIC8-1
LCMT1	ENST00000380962.9 link	n.*599C>A		non_coding_transcript_exon_variant	Exon 9 of 12	2		ENSP00000370349.5	H7BYF0
LCMT1	ENST00000380962.9 link	n.*599C>A		3_prime_UTR_variant	Exon 9 of 12	2		ENSP00000370349.5	H7BYF0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249156

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461238

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111748

Other (OTH)

AF:

0.00

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.742C>A (p.R248S) alteration is located in exon 8 (coding exon 8) of the LCMT1 gene. This alteration results from a C to A substitution at nucleotide position 742, causing the arginine (R) at amino acid position 248 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Benign

0.67

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.092

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Benign

-0.74

MutationAssessor

Pathogenic

4.0

H;.

PhyloP100

1.3

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.79

Loss of catalytic residue at R248 (P = 0.0427);.;

MVP

0.45

MPC

0.92

ClinPred

0.95

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.84

Mutation Taster

=21/79

disease causing

(source)

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

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16-25169163-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over