chr22-40857200-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPNPEP3	NM_022098.4	c.19G>T	p.Ala7Ser	missense_variant	Exon 1 of 10	ENST00000357137.9	NP_071381.1
XPNPEP3	NM_001204827.2	c.19G>T	p.Ala7Ser	missense_variant	Exon 1 of 3		NP_001191756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPNPEP3	ENST00000357137.9	c.19G>T	p.Ala7Ser	missense_variant	Exon 1 of 10	1	NM_022098.4	ENSP00000349658.4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.32	N;.
REVEL	Benign	0.13
Sift	Benign	0.12	T;.
Sift4G	Benign	0.39	T;D
Polyphen		0.084	B;.
Vest4		0.25
MutPred		0.29		Gain of disorder (P = 0.0193);Gain of disorder (P = 0.0193);
MVP		0.27
MPC		0.14
ClinPred		0.21	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.056
gMVP		0.49

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-41253204; COSMIC: COSV53420644; COSMIC: COSV53420644;