chr22-40869045-A-C

Variant names:

• chr22-40869045-A-C
• NM_022098.4:c.111A>C
• XPNPEP3 p.Pro37Pro

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_022098.4(XPNPEP3):​c.111A>C​(p.Pro37Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P37P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPNPEP3 NM_022098.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.347
• Publications: 0 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: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• late-onset nephronophthisis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP7: Synonymous conserved (PhyloP=-0.347 with no splicing effect.

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.111A>C	p.Pro37Pro	synonymous	Exon 2 of 10	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.111A>C	p.Pro37Pro	synonymous	Exon 2 of 10	ENSP00000349658.4	Q9NQH7-1
	XPNPEP3	ENST00000926395.1		c.111A>C	p.Pro37Pro	synonymous	Exon 2 of 9	ENSP00000596454.1
	XPNPEP3	ENST00000904509.1		c.111A>C	p.Pro37Pro	synonymous	Exon 2 of 8	ENSP00000574568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.6
DANN	Benign	0.60
PhyloP100		-0.35
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

hg19: chr22-41265049;