rs374129317

Variant names:

• chr22-40857138-C-T
• rs374129317
• ENST00000482652.1:n.42C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-40857138-C-T
• chr22-40857138-C-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000904508.1(XPNPEP3):​c.-44C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,610,020 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (5 hom.)
• Consequence: XPNPEP3 ENST00000904508.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.34
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000696 (106/152336) while in subpopulation AMR AF = 0.00098 (15/15308). AF 95% confidence interval is 0.000703. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000904508.1. 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.-44C>T		upstream_gene	N/A	NP_071381.1	Q9NQH7-1
	XPNPEP3	NM_001204827.2		c.-44C>T		upstream_gene	N/A	NP_001191756.1	A0A087X0Z2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPNPEP3	ENST00000482652.1	TSL:1	n.42C>T		non_coding_transcript_exon	Exon 1 of 3
	XPNPEP3	ENST00000904508.1		c.-44C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000574567.1
	XPNPEP3	ENST00000904509.1		c.-44C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000574568.1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000627 AC: 153 AN: 243980 AF XY: 0.000626

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.000814

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000529 AC: 771 AN: 1457684 Hom.: 5 Cov.: 31 AF XY: 0.000543 AC XY: 394 AN XY: 725090

African (AFR) AF: 0.000659 AC: 22 AN: 33368

American (AMR) AF: 0.000943 AC: 42 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.000923 AC: 24 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.000513 AC: 44 AN: 85852

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52894

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5766

European-Non Finnish (NFE) AF: 0.000458 AC: 508 AN: 1109568

Other (OTH) AF: 0.00116 AC: 70 AN: 60196

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74484

African (AFR) AF: 0.000289 AC: 12 AN: 41582

American (AMR) AF: 0.000980 AC: 15 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68024

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000727 Hom.: 0

Bravo AF: 0.000737

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Nephronophthisis-Like Nephropathy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.035
DANN	Benign	0.84
PhyloP100		-3.3
PromoterAI		0.0036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs374129317; hg19: chr22-41253142;