rs121434529

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_000262.3(NAGA):​c.973G>T​(p.Glu325*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 6.8e-7 ( 0 hom. )

Consequence

NAGA
NM_000262.3 stop_gained

Scores

4
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.96
Variant links:
Genes affected
NAGA (HGNC:7631): (alpha-N-acetylgalactosaminidase) NAGA encodes the lysosomal enzyme alpha-N-acetylgalactosaminidase, which cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates. Mutations in NAGA have been identified as the cause of Schindler disease types I and II (type II also known as Kanzaki disease). [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.213 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NAGANM_000262.3 linkc.973G>T p.Glu325* stop_gained Exon 8 of 9 ENST00000396398.8 NP_000253.1 P17050A0A024R1Q5
NAGANM_001362848.1 linkc.973G>T p.Glu325* stop_gained Exon 9 of 10 NP_001349777.1
NAGANM_001362850.1 linkc.973G>T p.Glu325* stop_gained Exon 9 of 10 NP_001349779.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NAGAENST00000396398.8 linkc.973G>T p.Glu325* stop_gained Exon 8 of 9 1 NM_000262.3 ENSP00000379680.3 P17050
NAGAENST00000402937.1 linkc.973G>T p.Glu325* stop_gained Exon 9 of 10 5 ENSP00000384603.1 P17050
NAGAENST00000403363.5 linkc.973G>T p.Glu325* stop_gained Exon 9 of 10 5 ENSP00000385283.1 P17050

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461826
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727214
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:
8.99e-7
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
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
39
DANN
Uncertain
0.99
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.96
D
Vest4
0.94
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.24
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.24
Position offset: -30
DS_AL_spliceai
0.24
Position offset: 15

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: chr22-42457056; API