Genetic Variant NAGA:c.*1333T>C (chr22-42058946-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0280

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NAGA	NM_000262.3 link	c.*1333T>C	3_prime_UTR_variant	Exon 9 of 9	ENST00000396398.8	NP_000253.1	P17050A0A024R1Q5
NAGA	NM_001362848.1 link	c.*1333T>C	3_prime_UTR_variant	Exon 10 of 10		NP_001349777.1
NAGA	NM_001362850.1 link	c.*1333T>C	3_prime_UTR_variant	Exon 10 of 10		NP_001349779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGA	ENST00000396398 link	c.*1333T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_000262.3	ENSP00000379680.3		P17050

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60161

AN:

152040

Hom.:

14425

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

0.444

AC XY:

AN XY:

show subpopulations

Gnomad4 NFE exome

AF:

0.500

GnomAD4 genome

AF:

0.395

AC:

60178

AN:

152158

Hom.:

14435

Cov.:

AF XY:

0.404

AC XY:

30077

AN XY:

74380

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha-N-acetylgalactosaminidase deficiency type 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over