rs143719656

Variant names:

• chr22-40886305-A-G
• rs143719656
• NM_022098.4:c.590-8A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-40886305-A-G
• chr22-40886305-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022098.4(XPNPEP3):​c.590-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,842 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (8 hom.)
• Consequence: XPNPEP3 NM_022098.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002867
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.464
• Publications: 1 publications found

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]

XPNPEP3 Gene-Disease associations (from GenCC):

• nephronophthisis-like nephropathy 1

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• late-onset nephronophthisis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-40886305-A-G is Benign according to our data. Variant chr22-40886305-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167851.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00149 (227/152238) while in subpopulation NFE AF = 0.00263 (179/68018). AF 95% confidence interval is 0.00232. There are 2 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPNPEP3	NM_022098.4	c.590-8A>G		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000357137.9	NP_071381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPNPEP3	ENST00000357137.9	c.590-8A>G		splice_region_variant, intron_variant	Intron 3 of 9	1	NM_022098.4	ENSP00000349658.4
XPNPEP3	ENST00000428799.1	n.*472-8A>G		splice_region_variant, intron_variant	Intron 4 of 10	2		ENSP00000394283.1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152120 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00137 AC: 345 AN: 250944 AF XY: 0.00129

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00208 AC: 3038 AN: 1461604 Hom.: 8 Cov.: 31 AF XY: 0.00209 AC XY: 1522 AN XY: 727110

African (AFR) AF: 0.000209 AC: 7 AN: 33472

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 115 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86248

European-Finnish (FIN) AF: 0.000488 AC: 26 AN: 53328

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5656

European-Non Finnish (NFE) AF: 0.00246 AC: 2740 AN: 1111966

Other (OTH) AF: 0.00157 AC: 95 AN: 60380

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152238 Hom.: 2 Cov.: 31 AF XY: 0.00120 AC XY: 89 AN XY: 74438

African (AFR) AF: 0.000409 AC: 17 AN: 41552

American (AMR) AF: 0.000720 AC: 11 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00263 AC: 179 AN: 68018

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00146

EpiCase AF: 0.00278

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Feb 13, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nephronophthisis-like nephropathy 1 Uncertain:1 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.44
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs143719656; hg19: chr22-41282309;