22-42066730-C-G

Variant names:

• chr22-42066730-C-G
• rs121434531
• NM_000262.3:c.577G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000262.3(NAGA):​c.577G>C​(p.Glu193Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,603,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NAGA NM_000262.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43
• Publications: 4 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23560485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGA	NM_000262.3	c.577G>C	p.Glu193Gln	missense_variant	Exon 5 of 9	ENST00000396398.8	NP_000253.1
NAGA	NM_001362848.1	c.577G>C	p.Glu193Gln	missense_variant	Exon 6 of 10		NP_001349777.1
NAGA	NM_001362850.1	c.577G>C	p.Glu193Gln	missense_variant	Exon 6 of 10		NP_001349779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGA	ENST00000396398.8	c.577G>C	p.Glu193Gln	missense_variant	Exon 5 of 9	1	NM_000262.3	ENSP00000379680.3
NAGA	ENST00000402937.1	c.577G>C	p.Glu193Gln	missense_variant	Exon 6 of 10	5		ENSP00000384603.1
NAGA	ENST00000403363.5	c.577G>C	p.Glu193Gln	missense_variant	Exon 6 of 10	5		ENSP00000385283.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000439 AC: 1 AN: 227710 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000983

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451376 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720966

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 43114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39340

South Asian (SAS) AF: 0.00 AC: 0 AN: 84346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107506

Other (OTH) AF: 0.00 AC: 0 AN: 59926

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.096
DEOGEN2	Uncertain	0.54	D;D;D
Eigen	Benign	0.045
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.030	N;N;N
PhyloP100		3.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.74	N;N;N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.24
MutPred		0.41		Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);
MVP		0.97
MPC		0.20
ClinPred		0.087	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.85
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121434531; hg19: chr22-42462734;