4-17577477-G-A

Variant names:

• chr4-17577477-G-A
• rs746748058
• NM_015907.3:c.12G>A
• LAP3 p.Leu4Leu

Variant summary

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

The NM_015907.3(LAP3):​c.12G>A​(p.Leu4Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,426,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: LAP3 NM_015907.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.87
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).

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.12G>A	p.Leu4Leu	synonymous	Exon 1 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.12G>A	p.Leu4Leu	synonymous	Exon 1 of 13	ENSP00000226299.4	P28838-1
	LAP3	ENST00000618908.4	TSL:1	c.12G>A	p.Leu4Leu	synonymous	Exon 1 of 13	ENSP00000481000.1	P28838-1
	LAP3	ENST00000955710.1		c.12G>A	p.Leu4Leu	synonymous	Exon 1 of 11	ENSP00000625769.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000100 AC: 2 AN: 199522 AF XY: 0.00

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: 0.0000231

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1426924 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 707328

⚠️ 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: 32200

American (AMR) AF: 0.00 AC: 0 AN: 40198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25398

East Asian (EAS) AF: 0.00 AC: 0 AN: 37636

South Asian (SAS) AF: 0.00 AC: 0 AN: 81630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4168

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1096404

Other (OTH) AF: 0.00 AC: 0 AN: 58898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0332287), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.97
PhyloP100		2.9
PromoterAI		0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs746748058;

hg19: chr4-17579100;