rs73167107

Variant names:

• chr22-42067809-C-T
• rs73167107
• NM_000262.3:c.280G>A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000262.3(NAGA):​c.280G>A​(p.Asp94Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,612,702 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: NAGA NM_000262.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 6.17

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09071505).
• BP6: Variant 22-42067809-C-T is Benign according to our data. Variant chr22-42067809-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 341912.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}. Variant chr22-42067809-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00121 (184/152304) while in subpopulation NFE AF= 0.00201 (137/68030). AF 95% confidence interval is 0.00174. There are 2 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGA	NM_000262.3	c.280G>A	p.Asp94Asn	missense_variant	Exon 3 of 9	ENST00000396398.8	NP_000253.1
NAGA	NM_001362848.1	c.280G>A	p.Asp94Asn	missense_variant	Exon 4 of 10		NP_001349777.1
NAGA	NM_001362850.1	c.280G>A	p.Asp94Asn	missense_variant	Exon 4 of 10		NP_001349779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGA	ENST00000396398.8	c.280G>A	p.Asp94Asn	missense_variant	Exon 3 of 9	1	NM_000262.3	ENSP00000379680.3
NAGA	ENST00000402937.1	c.280G>A	p.Asp94Asn	missense_variant	Exon 4 of 10	5		ENSP00000384603.1
NAGA	ENST00000403363.5	c.280G>A	p.Asp94Asn	missense_variant	Exon 4 of 10	5		ENSP00000385283.1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152186 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00132 AC: 331 AN: 250106 Hom.: 1 AF XY: 0.00126 AC XY: 171 AN XY: 135262

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000344

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00184 AC: 2694 AN: 1460398 Hom.: 5 Cov.: 30 AF XY: 0.00174 AC XY: 1263 AN XY: 726558

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000651

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152304 Hom.: 2 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74472

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0356 Hom.: 1473

Bravo AF: 0.00134

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00125 AC: 152

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Feb 18, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NAGA: BP4, BS2 -

Jan 13, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alpha-N-acetylgalactosaminidase deficiency type 2 Uncertain:2

Jan 18, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Alpha-N-acetylgalactosaminidase deficiency type 1 Uncertain:1 Benign:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Alpha-N-acetylgalactosaminidase deficiency type 2;C1836544:Alpha-N-acetylgalactosaminidase deficiency type 1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NAGA-related disorder Benign:1

Feb 08, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.11	B;B;B
Vest4		0.68
MVP		0.87
MPC		0.35
ClinPred		0.055	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.91

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: rs73167107; hg19: chr22-42463813; COSMIC: COSV67169793;