NM_000262.3:c.*555C>T

Variant names:

• chr22-42059724-G-A
• rs141688392
• NM_000262.3:c.*555C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000262.3(NAGA):​c.*555C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 163,826 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: NAGA NM_000262.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.158
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-42059724-G-A is Benign according to our data. Variant chr22-42059724-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 341897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00163 (248/152284) while in subpopulation AMR AF = 0.0036 (55/15298). AF 95% confidence interval is 0.00284. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*555C>T		3_prime_UTR	Exon 9 of 9	NP_000253.1	P17050
	NAGA	NM_001362848.1		c.*555C>T		3_prime_UTR	Exon 10 of 10	NP_001349777.1	P17050
	NAGA	NM_001362850.1		c.*555C>T		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.*555C>T		3_prime_UTR	Exon 9 of 9	ENSP00000379680.3	P17050
	NAGA	ENST00000898671.1		c.*555C>T		3_prime_UTR	Exon 9 of 9	ENSP00000568730.1
	NAGA	ENST00000898673.1		c.*555C>T		3_prime_UTR	Exon 9 of 9	ENSP00000568732.1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00104 AC: 12 AN: 11542 Hom.: 0 Cov.: 0 AF XY: 0.000981 AC XY: 6 AN XY: 6118

African (AFR) AF: 0.00 AC: 0 AN: 234

American (AMR) AF: 0.00295 AC: 7 AN: 2372

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 1 AN: 112

East Asian (EAS) AF: 0.00 AC: 0 AN: 752

South Asian (SAS) AF: 0.00 AC: 0 AN: 1534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 18

European-Non Finnish (NFE) AF: 0.000507 AC: 3 AN: 5914

Other (OTH) AF: 0.00237 AC: 1 AN: 422

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74460

African (AFR) AF: 0.00111 AC: 46 AN: 41548

American (AMR) AF: 0.00360 AC: 55 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00206

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Alpha-N-acetylgalactosaminidase deficiency type 1 (1)
-	-	1	Alpha-N-acetylgalactosaminidase deficiency type 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.4
DANN	Benign	0.42
PhyloP100		0.16

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: rs141688392; hg19: chr22-42455728;