Genetic Variant LAP3:p.Lys321Asn (chr4-17595509-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015907.3(LAP3):c.963G>C(p.Lys321Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LAP3
NM_015907.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0360

Publications

0 publications found

Variant links:

Genes affected

LAP3 (HGNC:18449): (leucine aminopeptidase 3) Predicted to enable peptidase activity. Predicted to be involved in proteolysis. Located in cytosol; midbody; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LAP3 links:

MED28-DT (HGNC:55567): (MED28 divergent transcript)

MED28-DT links:

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ACMG classification

Classification was made for transcript

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=0.26466423).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015907.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAP3	NM_015907.3	MANE Select	c.963G>C	p.Lys321Asn	missense	Exon 8 of 13	NP_056991.2
MED28-DT	NR_186330.1		n.547-7028C>G		intron	N/A
MED28-DT	NR_186331.1		n.547-7830C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAP3	ENST00000226299.9	TSL:1 MANE Select	c.963G>C	p.Lys321Asn	missense	Exon 8 of 13	ENSP00000226299.4	P28838-1
LAP3	ENST00000618908.4	TSL:1	c.963G>C	p.Lys321Asn	missense	Exon 8 of 13	ENSP00000481000.1	P28838-1
LAP3	ENST00000606142.5	TSL:1	c.870G>C	p.Lys290Asn	missense	Exon 8 of 13	ENSP00000476028.1	P28838-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111934

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.0095

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.96

MutationAssessor

Benign

2.0

PhyloP100

-0.036

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.5

REVEL

Benign

0.075

Sift

Benign

0.12

Sift4G

Benign

0.28

Polyphen

0.010

Vest4

0.33

MutPred

0.51

Loss of ubiquitination at K321 (P = 0.0283)

MVP

0.61

MPC

0.28

ClinPred

0.22

GERP RS

2.0

Varity_R

0.076

gMVP

0.76

Mutation Taster

=94/6

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over