22-40857200-G-T

Variant names:

• chr22-40857200-G-T
• rs771071055
• NM_022098.4:c.19G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022098.4(XPNPEP3):​c.19G>T​(p.Ala7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: XPNPEP3 NM_022098.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.139
• 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: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• late-onset nephronophthisis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05328107).

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.19G>T	p.Ala7Ser	missense	Exon 1 of 10	NP_071381.1	Q9NQH7-1
	XPNPEP3	NM_001204827.2		c.19G>T	p.Ala7Ser	missense	Exon 1 of 3	NP_001191756.1	A0A087X0Z2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPNPEP3	ENST00000357137.9	TSL:1 MANE Select	c.19G>T	p.Ala7Ser	missense	Exon 1 of 10	ENSP00000349658.4	Q9NQH7-1
	XPNPEP3	ENST00000482652.1	TSL:1	n.104G>T		non_coding_transcript_exon	Exon 1 of 3
	XPNPEP3	ENST00000926395.1		c.19G>T	p.Ala7Ser	missense	Exon 1 of 9	ENSP00000596454.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.14
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.39	T
Polyphen		0.084	B
Vest4		0.25
MutPred		0.29		Gain of disorder (P = 0.0193)
MVP		0.27
MPC		0.14
ClinPred		0.21	T
GERP RS		-2.4
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.056
gMVP		0.49
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs771071055; hg19: chr22-41253204; COSMIC: COSV53420644; COSMIC: COSV53420644;