rs5758111

Positions:

• chr22-40860676-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1 BA1

The NM_001204827.2(XPNPEP3):​c.65-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,218,696 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0026 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (29 hom.)
• Consequence: XPNPEP3 NM_001204827.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00001992
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960

Genes affected

DNAJB7 (HGNC:24986): (DnaJ heat shock protein family (Hsp40) member B7) The protein encoded by this intronless gene belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus; a glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain containing 4 motifs resembling a zinc finger domain.[provided by RefSeq, Mar 2011]

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.8, offset of -4, new splice context is: tccttttttttttttttaAGacg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJB7	NM_145174.2	c.*389T>C		3_prime_UTR_variant	1/1	ENST00000307221.5	NP_660157.1
XPNPEP3	NM_022098.4	c.64+3431A>G		intron_variant		ENST00000357137.9	NP_071381.1
XPNPEP3	NM_001204827.2	c.65-2A>G		splice_acceptor_variant, intron_variant			NP_001191756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJB7	ENST00000307221	c.*389T>C		3_prime_UTR_variant	1/1		NM_145174.2	ENSP00000307197.4
XPNPEP3	ENST00000357137.9	c.64+3431A>G		intron_variant		1	NM_022098.4	ENSP00000349658.4

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 390 AN: 151348 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.000680

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0571

Gnomad SAS AF: 0.00437

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00352 AC: 329 AN: 93542 Hom.: 4 AF XY: 0.00318 AC XY: 166 AN XY: 52148

Gnomad AFR exome AF: 0.000441

Gnomad AMR exome AF: 0.000269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0424

Gnomad SAS exome AF: 0.00165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00553

GnomAD4 exome AF: 0.00136 AC: 1456 AN: 1067230 Hom.: 29 Cov.: 16 AF XY: 0.00133 AC XY: 714 AN XY: 535728

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0293

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.0000310

Gnomad4 NFE exome AF: 0.0000318

Gnomad4 OTH exome AF: 0.00746

GnomAD4 genome AF: 0.00257 AC: 389 AN: 151466 Hom.: 17 Cov.: 32 AF XY: 0.00278 AC XY: 206 AN XY: 74010

Gnomad4 AFR AF: 0.000678

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0571

Gnomad4 SAS AF: 0.00416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.000856 Hom.: 0

Bravo AF: 0.00238

ExAC AF: 0.00195 AC: 30

Asia WGS AF: 0.0380 AC: 133 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.54
FATHMM_MKL	Benign	0.0093	N
GERP RS		-0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs5758111; hg19: chr22-41256680; COSMIC: COSV53424186; COSMIC: COSV53424186;