NM_000262.3:c.*170G>A

Variant names:

• chr22-42060109-C-T
• rs142863061
• NM_000262.3:c.*170G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000262.3(NAGA):​c.*170G>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 0.00159 in 862,014 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (2 hom.)
• Consequence: NAGA NM_000262.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.179
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-42060109-C-T is Benign according to our data. Variant chr22-42060109-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 900385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00578 (880/152228) while in subpopulation AFR AF = 0.02 (830/41538). AF 95% confidence interval is 0.0189. There are 7 homozygotes in GnomAd4. There are 442 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.*170G>A		3_prime_UTR	Exon 9 of 9	NP_000253.1	P17050
	NAGA	NM_001362848.1		c.*170G>A		3_prime_UTR	Exon 10 of 10	NP_001349777.1	P17050
	NAGA	NM_001362850.1		c.*170G>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.*170G>A		3_prime_UTR	Exon 9 of 9	ENSP00000379680.3	P17050
	NAGA	ENST00000898675.1		c.*170G>A		3_prime_UTR	Exon 10 of 10	ENSP00000568734.1
	NAGA	ENST00000402937.1	TSL:5	c.*170G>A		3_prime_UTR	Exon 10 of 10	ENSP00000384603.1	P17050

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 868 AN: 152110 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00240

GnomAD4 exome AF: 0.000688 AC: 488 AN: 709786 Hom.: 2 Cov.: 9 AF XY: 0.000555 AC XY: 205 AN XY: 369532

African (AFR) AF: 0.0175 AC: 323 AN: 18452

American (AMR) AF: 0.00206 AC: 69 AN: 33572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18124

East Asian (EAS) AF: 0.000873 AC: 29 AN: 33216

South Asian (SAS) AF: 0.0000484 AC: 3 AN: 62026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33676

Middle Eastern (MID) AF: 0.000385 AC: 1 AN: 2596

European-Non Finnish (NFE) AF: 0.0000338 AC: 16 AN: 473066

Other (OTH) AF: 0.00134 AC: 47 AN: 35058

GnomAD4 genome AF: 0.00578 AC: 880 AN: 152228 Hom.: 7 Cov.: 32 AF XY: 0.00594 AC XY: 442 AN XY: 74432

African (AFR) AF: 0.0200 AC: 830 AN: 41538

American (AMR) AF: 0.00249 AC: 38 AN: 15290

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

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00497 Hom.: 0

Bravo AF: 0.00668

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/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	-0.79
CADD	Benign	4.5
DANN	Benign	0.76
PhyloP100		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs142863061; hg19: chr22-42456113;