chr22-42061052-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGA	NM_000262.3	c.973G>C	p.Glu325Gln	missense_variant	Exon 8 of 9	ENST00000396398.8	NP_000253.1
NAGA	NM_001362848.1	c.973G>C	p.Glu325Gln	missense_variant	Exon 9 of 10		NP_001349777.1
NAGA	NM_001362850.1	c.973G>C	p.Glu325Gln	missense_variant	Exon 9 of 10		NP_001349779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGA	ENST00000396398.8	c.973G>C	p.Glu325Gln	missense_variant	Exon 8 of 9	1	NM_000262.3	ENSP00000379680.3
NAGA	ENST00000402937.1	c.973G>C	p.Glu325Gln	missense_variant	Exon 9 of 10	5		ENSP00000384603.1
NAGA	ENST00000403363.5	c.973G>C	p.Glu325Gln	missense_variant	Exon 9 of 10	5		ENSP00000385283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;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;T;T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.3	L;L;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.071	T;T;T
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.027	B;B;B
Vest4		0.33
MutPred		0.56		Gain of MoRF binding (P = 0.0189);Gain of MoRF binding (P = 0.0189);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-42457056;