chr22-42059707-C-T

Variant names:

• chr22-42059707-C-T
• rs538578699
• NM_000262.3:c.*572G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000262.3(NAGA):​c.*572G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 160,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: NAGA NM_000262.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.24
• 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: Genomics England PanelApp, G2P, Orphanet
• alpha-N-acetylgalactosaminidase deficiency type 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000184 (28/152234) while in subpopulation EAS AF = 0.00231 (12/5184). AF 95% confidence interval is 0.00134. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGA	NM_000262.3	MANE Select	c.*572G>A		3_prime_UTR	Exon 9 of 9	NP_000253.1	P17050
	NAGA	NM_001362848.1		c.*572G>A		3_prime_UTR	Exon 10 of 10	NP_001349777.1	P17050
	NAGA	NM_001362850.1		c.*572G>A		3_prime_UTR	Exon 10 of 10	NP_001349779.1	P17050

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGA	ENST00000396398.8	TSL:1 MANE Select	c.*572G>A		3_prime_UTR	Exon 9 of 9	ENSP00000379680.3	P17050
	NAGA	ENST00000898671.1		c.*572G>A		3_prime_UTR	Exon 9 of 9	ENSP00000568730.1
	NAGA	ENST00000898673.1		c.*572G>A		3_prime_UTR	Exon 9 of 9	ENSP00000568732.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 1 AN: 8510 Hom.: 0 Cov.: 0 AF XY: 0.000223 AC XY: 1 AN XY: 4488

African (AFR) AF: 0.00 AC: 0 AN: 116

American (AMR) AF: 0.00 AC: 0 AN: 2008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 64

East Asian (EAS) AF: 0.00 AC: 0 AN: 412

South Asian (SAS) AF: 0.000924 AC: 1 AN: 1082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 92

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 14

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4424

Other (OTH) AF: 0.00 AC: 0 AN: 298

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74432

African (AFR) AF: 0.0000481 AC: 2 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000174

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Alpha-N-acetylgalactosaminidase deficiency type 1 (1)
-	1	-	Alpha-N-acetylgalactosaminidase deficiency type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.45
DANN	Benign	0.56
PhyloP100		-1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs538578699; hg19: chr22-42455711;