22-42061052-C-T

Variant names:

• chr22-42061052-C-T
• rs121434529
• NM_000262.3:c.973G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP3 PP5 BP4 BS1_Supporting BS2

The NM_000262.3(NAGA):​c.973G>A​(p.Glu325Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00365 in 1,614,138 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (12 hom.)
• Consequence: NAGA NM_000262.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:24 U:4
• Conservation: PhyloP100: 3.96
• Publications: 31 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: Orphanet, Genomics England PanelApp, G2P
• alpha-N-acetylgalactosaminidase deficiency type 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• alpha-N-acetylgalactosaminidase deficiency type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, M_CAP, MutationAssessor, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• PP5: Variant 22-42061052-C-T is Pathogenic according to our data. Variant chr22-42061052-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18162.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18690613). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00217 (331/152316) while in subpopulation NFE AF = 0.00381 (259/68034). AF 95% confidence interval is 0.00343. There are 0 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGA	NM_000262.3	MANE Select	c.973G>A	p.Glu325Lys	missense	Exon 8 of 9	NP_000253.1
	NAGA	NM_001362848.1		c.973G>A	p.Glu325Lys	missense	Exon 9 of 10	NP_001349777.1
	NAGA	NM_001362850.1		c.973G>A	p.Glu325Lys	missense	Exon 9 of 10	NP_001349779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGA	ENST00000396398.8	TSL:1 MANE Select	c.973G>A	p.Glu325Lys	missense	Exon 8 of 9	ENSP00000379680.3
	NAGA	ENST00000402937.1	TSL:5	c.973G>A	p.Glu325Lys	missense	Exon 9 of 10	ENSP00000384603.1
	NAGA	ENST00000403363.5	TSL:5	c.973G>A	p.Glu325Lys	missense	Exon 9 of 10	ENSP00000385283.1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 331 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00247 AC: 622 AN: 251354 AF XY: 0.00261

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00401

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00380 AC: 5559 AN: 1461822 Hom.: 12 Cov.: 32 AF XY: 0.00377 AC XY: 2739 AN XY: 727214

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00245 AC: 211 AN: 86256

European-Finnish (FIN) AF: 0.00140 AC: 75 AN: 53382

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00451 AC: 5012 AN: 1111986

Other (OTH) AF: 0.00316 AC: 191 AN: 60392

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74480

African (AFR) AF: 0.000746 AC: 31 AN: 41558

American (AMR) AF: 0.000849 AC: 13 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

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

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00381 AC: 259 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00361 Hom.: 7

Bravo AF: 0.00223

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00250 AC: 304

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00385

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	1	-	Alpha-N-acetylgalactosaminidase deficiency type 1 (7)
7	-	-	not provided (7)
3	1	-	Alpha-N-acetylgalactosaminidase deficiency type 2 (4)
2	-	-	Alpha-N-acetylgalactosaminidase deficiency (2)
2	-	-	Alpha-N-acetylgalactosaminidase deficiency type 2;C1836544:Alpha-N-acetylgalactosaminidase deficiency type 1 (2)
1	1	-	not specified (2)
1	-	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)
1	-	-	NAGA-related disorder (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.19	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		4.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.026	D
Polyphen		0.31	B
Vest4		0.93
MVP		0.98
MPC		0.54
ClinPred		0.13	T
GERP RS		5.7
Varity_R		0.90
gMVP		0.86
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs121434529; hg19: chr22-42457056; COSMIC: COSV104433504; COSMIC: COSV104433504;