rs121434529

Variant names:

• chr22-42061052-C-A
• rs121434529
• NM_000262.3:c.973G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-42061052-C-A
• chr22-42061052-C-G
• chr22-42061052-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NAGA NM_000262.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• Publications: 0 publications found

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]

NAGA Gene-Disease associations (from GenCC):

• alpha-N-acetylgalactosaminidase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• alpha-N-acetylgalactosaminidase deficiency type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• alpha-N-acetylgalactosaminidase deficiency type 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• alpha-N-acetylgalactosaminidase deficiency type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000262.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGA	NM_000262.3	MANE Select	c.973G>T	p.Glu325*	stop_gained	Exon 8 of 9	NP_000253.1
	NAGA	NM_001362848.1		c.973G>T	p.Glu325*	stop_gained	Exon 9 of 10	NP_001349777.1
	NAGA	NM_001362850.1		c.973G>T	p.Glu325*	stop_gained	Exon 9 of 10	NP_001349779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGA	ENST00000396398.8	TSL:1 MANE Select	c.973G>T	p.Glu325*	stop_gained	Exon 8 of 9	ENSP00000379680.3
	NAGA	ENST00000402937.1	TSL:5	c.973G>T	p.Glu325*	stop_gained	Exon 9 of 10	ENSP00000384603.1
	NAGA	ENST00000403363.5	TSL:5	c.973G>T	p.Glu325*	stop_gained	Exon 9 of 10	ENSP00000385283.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.0
Vest4		0.94
GERP RS		5.7
Mutation Taster		=2/198	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs121434529; hg19: chr22-42457056;