22-40857244-A-G
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2PP3BP6_Very_StrongBS1
The NM_022098.4(XPNPEP3):āc.63A>Gā(p.Ser21=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000123 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.00064 ( 0 hom., cov: 32)
Exomes š: 0.000069 ( 0 hom. )
Consequence
XPNPEP3
NM_022098.4 splice_region, synonymous
NM_022098.4 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9983
2
Clinical Significance
Conservation
PhyloP100: 4.43
Genes affected
XPNPEP3 (HGNC:28052): (X-prolyl aminopeptidase 3) The protein encoded by this gene belongs to the family of X-pro-aminopeptidases that utilize a metal cofactor, and remove the N-terminal amino acid from peptides with a proline residue in the penultimate position. This protein has been shown to localize to the mitochondria of renal cells, and have a role in ciliary function. Mutations in this gene are associated with nephronophthisis-like nephropathy-1. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene, however, expression of some of these isoforms in vivo is not known.[provided by RefSeq, Mar 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
BP6
Variant 22-40857244-A-G is Benign according to our data. Variant chr22-40857244-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 341666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000637 (97/152312) while in subpopulation AFR AF= 0.00224 (93/41578). AF 95% confidence interval is 0.00187. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| XPNPEP3 | NM_022098.4 | c.63A>G | p.Ser21= | splice_region_variant, synonymous_variant | 1/10 | ENST00000357137.9 | |
| XPNPEP3 | NM_001204827.2 | c.63A>G | p.Ser21= | splice_region_variant, synonymous_variant | 1/3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| XPNPEP3 | ENST00000357137.9 | c.63A>G | p.Ser21= | splice_region_variant, synonymous_variant | 1/10 | 1 | NM_022098.4 | P1 |
Frequencies
GnomAD3 genomes 0.000637 AC: 97AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000215 AC: 54AN: 250832Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135676
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GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461802Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727184
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GnomAD4 genome 0.000637 AC: 97AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43AN XY: 74490
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Nephronophthisis-like nephropathy 1 Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 19, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at