17-80470947-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PS1_ModeratePM1PP5_Very_StrongBP4

The NM_002522.4(NPTX1):​c.1165G>A​(p.Gly389Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NPTX1
NM_002522.4 missense

Scores

6
13

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.02
Variant links:
Genes affected
NPTX1 (HGNC:7952): (neuronal pentraxin 1) NPTX1 is a member of the neuronal pentraxin gene family. Neuronal pentraxin 1 is similar to the rat NP1 gene which encodes a binding protein for the snake venom toxin taipoxin. Human NPTX1 mRNA is exclusively localized to the nervous system. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS1
Transcript NM_002522.4 (NPTX1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a domain Pentraxin (PTX) (size 202) in uniprot entity NPTX1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002522.4
PP5
Variant 17-80470947-C-T is Pathogenic according to our data. Variant chr17-80470947-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1184956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.3369773). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPTX1NM_002522.4 linkc.1165G>A p.Gly389Arg missense_variant Exon 5 of 5 ENST00000306773.5 NP_002513.2 Q15818

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPTX1ENST00000306773.5 linkc.1165G>A p.Gly389Arg missense_variant Exon 5 of 5 1 NM_002522.4 ENSP00000307549.4 Q15818
NPTX1ENST00000571100.2 linkc.451G>A p.Gly151Arg missense_variant Exon 4 of 4 4 ENSP00000511957.1 A0A8Q3WL24
NPTX1ENST00000535681.1 linkn.1767G>A non_coding_transcript_exon_variant Exon 3 of 4 2
NPTX1ENST00000695485.1 linkn.588G>A non_coding_transcript_exon_variant Exon 4 of 4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152076
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251148
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135786
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461550
Hom.:
0
Cov.:
34
AF XY:
0.00000550
AC XY:
4
AN XY:
727038
show subpopulations
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:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152076
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Jun 17, 2021
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 08, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Segregates with disease in many affected individuals with features consistent with NPTX1- related spinocerebellar ataxia from several families in published literature (PMID: 34788392, 35288776); Published functional studies suggest a damaging effect on endoplasmic reticulum morphology and increased cytotoxicity (PMID: 34788392); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35288776, 34788392) -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NPTX1: PP1:Strong, PS4, PM2:Supporting, PP2, PS3:Supporting -

Spinocerebellar ataxia 50 Pathogenic:2
May 22, 2024
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 34788392). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001184956 /PMID: 34788392). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 34788392). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 20, 2022
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1
Oct 13, 2023
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1165G>A (p.G389R) alteration is located in exon 5 (coding exon 5) of the NPTX1 gene. This alteration results from a G to A substitution at nucleotide position 1165, causing the glycine (G) at amino acid position 389 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251148) total alleles studied. The highest observed frequency was 0.001% (1/113534) of European (non-Finnish) alleles. This alteration has been reported to segregate with disease in multiple families with features consistent with NPTX1-related cerebellar ataxia (Coutelier, 2022; Helmchen, 2022). This amino acid position is well conserved in available vertebrate species. Functional analysis demonstrated that the p.G389R variant increased aggregated endoplasmic reticulum morphology, triggered hyperplasia of the endoplasmic reticulum, induced ATF6-mediated endoplasmic reticulum stress, and increased cytotoxicity (Coutelier, 2022). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.079
T
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Benign
0.28
N
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.34
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.63
N
REVEL
Benign
0.13
Sift
Benign
0.14
T
Sift4G
Benign
0.21
T
Polyphen
1.0
D
Vest4
0.41
MutPred
0.32
Gain of solvent accessibility (P = 0.0306);
MVP
0.59
MPC
1.7
ClinPred
0.73
D
GERP RS
5.4
Varity_R
0.25

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1466750124; hg19: chr17-78444747; COSMIC: COSV60775223; COSMIC: COSV60775223; API