22-42061052-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000262.3(NAGA):​c.973G>C​(p.Glu325Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E325K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAGA NM_000262.3 missense
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-42061052-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18162.

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>C	p.Glu325Gln	missense	Exon 8 of 9	NP_000253.1
	NAGA	NM_001362848.1		c.973G>C	p.Glu325Gln	missense	Exon 9 of 10	NP_001349777.1
	NAGA	NM_001362850.1		c.973G>C	p.Glu325Gln	missense	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>C	p.Glu325Gln	missense	Exon 8 of 9	ENSP00000379680.3
	NAGA	ENST00000402937.1	TSL:5	c.973G>C	p.Glu325Gln	missense	Exon 9 of 10	ENSP00000384603.1
	NAGA	ENST00000403363.5	TSL:5	c.973G>C	p.Glu325Gln	missense	Exon 9 of 10	ENSP00000385283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.079
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.3	L
PhyloP100		4.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.57
Sift	Benign	0.071	T
Sift4G	Uncertain	0.056	T
Polyphen		0.027	B
Vest4		0.33
MutPred		0.56		Gain of MoRF binding (P = 0.0189)
MVP		0.98
MPC		0.22
ClinPred		0.59	D
GERP RS		5.7
Varity_R		0.72
gMVP		0.72
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434529; hg19: chr22-42457056;