rs1894658

Positions:

• chr22-40869045-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022098.4(XPNPEP3):​c.111A>G​(p.Pro37=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,614,120 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (66 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (58 hom.)
• Consequence: XPNPEP3 NM_022098.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.347

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 22-40869045-A-G is Benign according to our data. Variant chr22-40869045-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 341667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.347 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPNPEP3	NM_022098.4	c.111A>G	p.Pro37=	synonymous_variant	2/10	ENST00000357137.9	NP_071381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPNPEP3	ENST00000357137.9	c.111A>G	p.Pro37=	synonymous_variant	2/10	1	NM_022098.4	ENSP00000349658	P1
XPNPEP3	ENST00000417688.5	n.216A>G		non_coding_transcript_exon_variant	2/3	3
XPNPEP3	ENST00000465258.1	n.461A>G		non_coding_transcript_exon_variant	2/3	3
XPNPEP3	ENST00000428799.1	c.111A>G	p.Pro37=	synonymous_variant, NMD_transcript_variant	2/11	2		ENSP00000394283

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2446 AN: 152160 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00409 AC: 1028 AN: 251488 Hom.: 30 AF XY: 0.00283 AC XY: 385 AN XY: 135922

Gnomad AFR exome AF: 0.0569

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00160 AC: 2342 AN: 1461842 Hom.: 58 Cov.: 31 AF XY: 0.00135 AC XY: 981 AN XY: 727232

Gnomad4 AFR exome AF: 0.0555

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.0161 AC: 2453 AN: 152278 Hom.: 66 Cov.: 32 AF XY: 0.0159 AC XY: 1187 AN XY: 74462

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00914 Hom.: 15

Bravo AF: 0.0181

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis-like nephropathy 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 29, 2021	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.7
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1894658; hg19: chr22-41265049;