4-17583624-C-G

Variant names:

• chr4-17583624-C-G
• rs374750225
• NM_015907.3:c.521C>G

Variant summary

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

The NM_015907.3(LAP3):​c.521C>G​(p.Ser174Trp) 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. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S174L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LAP3 NM_015907.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• Publications: 2 publications found

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]

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=0.36926022).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAP3	NM_015907.3	MANE Select	c.521C>G	p.Ser174Trp	missense	Exon 5 of 13	NP_056991.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAP3	ENST00000226299.9	TSL:1 MANE Select	c.521C>G	p.Ser174Trp	missense	Exon 5 of 13	ENSP00000226299.4	P28838-1
	LAP3	ENST00000618908.4	TSL:1	c.521C>G	p.Ser174Trp	missense	Exon 5 of 13	ENSP00000481000.1	P28838-1
	LAP3	ENST00000606142.5	TSL:1	c.428C>G	p.Ser143Trp	missense	Exon 5 of 13	ENSP00000476028.1	P28838-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251420 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.56
MutPred		0.40		Loss of disorder (P = 0.0018)
MVP		0.78
MPC		0.50
ClinPred		0.82	D
GERP RS		4.6
PromoterAI		-0.0062	Neutral
Varity_R		0.11
gMVP		0.44
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs374750225; hg19: chr4-17585247;