rs117568682

Variant names:

• chr22-40914230-T-C
• rs117568682
• NM_022098.4:c.970-9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022098.4(XPNPEP3):​c.970-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,258 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00067 (15 hom.)
• Consequence: XPNPEP3 NM_022098.4 intron
• Scores: Splicing: ADA: 0.002429
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.567
• Publications: 2 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: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• late-onset nephronophthisis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 22-40914230-T-C is Benign according to our data. Variant chr22-40914230-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000926 (141/152244) while in subpopulation EAS AF = 0.0236 (122/5178). AF 95% confidence interval is 0.0202. There are 2 homozygotes in GnomAd4. There are 88 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022098.4. 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
	XPNPEP3	NM_022098.4	MANE Select	c.970-9T>C		intron	N/A	NP_071381.1	Q9NQH7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPNPEP3	ENST00000357137.9	TSL:1 MANE Select	c.970-9T>C		intron	N/A	ENSP00000349658.4	Q9NQH7-1
	XPNPEP3	ENST00000926395.1		c.907-9T>C		intron	N/A	ENSP00000596454.1
	XPNPEP3	ENST00000904508.1		c.853-9T>C		intron	N/A	ENSP00000574567.1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152124 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00236 AC: 594 AN: 251464 AF XY: 0.00213

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0299

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000671 AC: 980 AN: 1461014 Hom.: 15 Cov.: 31 AF XY: 0.000653 AC XY: 475 AN XY: 726878

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0196 AC: 776 AN: 39686

South Asian (SAS) AF: 0.00135 AC: 116 AN: 86238

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

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

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111258

Other (OTH) AF: 0.00106 AC: 64 AN: 60358

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152244 Hom.: 2 Cov.: 31 AF XY: 0.00118 AC XY: 88 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0236 AC: 122 AN: 5178

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.00134

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nephronophthisis-like nephropathy 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.082
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: rs117568682; hg19: chr22-41310234;