22-42058946-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000262.3(NAGA):c.*1333T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 152,178 control chromosomes in the GnomAD database, including 14,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (14435 hom., cov: 32)
  • Exomes 𝑓: 0.50 (1 hom.)
• Consequence: NAGA NM_000262.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0280

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-42058946-A-G is Benign according to our data. Variant chr22-42058946-A-G is described in ClinVar as [Benign]. Clinvar id is 341891.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGA	NM_000262.3	c.*1333T>C		3_prime_UTR_variant	9/9	ENST00000396398.8
NAGA	NM_001362848.1	c.*1333T>C		3_prime_UTR_variant	10/10
NAGA	NM_001362850.1	c.*1333T>C		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGA	ENST00000396398.8	c.*1333T>C		3_prime_UTR_variant	9/9	1	NM_000262.3	P1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60161 AN: 152040 Hom.: 14425 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.416

GnomAD4 exome AF: 0.500 AC: 10 AN: 20 Hom.: 1 Cov.: 0 AF XY: 0.444 AC XY: 8 AN XY: 18

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.395 AC: 60178 AN: 152158 Hom.: 14435 Cov.: 32 AF XY: 0.404 AC XY: 30077 AN XY: 74380

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.509

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.849

Gnomad4 SAS AF: 0.507

Gnomad4 FIN AF: 0.514

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.422

Alfa AF: 0.456 Hom.: 16806

Bravo AF: 0.389

Asia WGS AF: 0.635 AC: 2206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Alpha-N-acetylgalactosaminidase deficiency type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Alpha-N-acetylgalactosaminidase deficiency type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.2
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1063392; hg19: chr22-42454950;