rs121434532

Variant names:

• chr22-42067136-G-C
• rs121434532
• NM_000262.3:c.479C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-42067136-G-C
• chr22-42067136-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5 BP4 BS1_Supporting

The NM_000262.3(NAGA):​c.479C>G​(p.Ser160Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000676 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S160S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: NAGA NM_000262.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:7
• Conservation: PhyloP100: 5.84
• Publications: 11 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: Likely_benign. The variant received -1 ACMG points.

• PP5: Variant 22-42067136-G-C is Pathogenic according to our data. Variant chr22-42067136-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18165.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24728158). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000479 (73/152268) while in subpopulation NFE AF = 0.000691 (47/68008). AF 95% confidence interval is 0.000534. There are 0 homozygotes in GnomAd4. There are 31 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

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.479C>G	p.Ser160Cys	missense	Exon 4 of 9	NP_000253.1	P17050
	NAGA	NM_001362848.1		c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	NP_001349777.1	P17050
	NAGA	NM_001362850.1		c.479C>G	p.Ser160Cys	missense	Exon 5 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.479C>G	p.Ser160Cys	missense	Exon 4 of 9	ENSP00000379680.3	P17050
	NAGA	ENST00000898675.1		c.479C>G	p.Ser160Cys	missense	Exon 4 of 10	ENSP00000568734.1
	NAGA	ENST00000402937.1	TSL:5	c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	ENSP00000384603.1	P17050

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000744 AC: 187 AN: 251336 AF XY: 0.000685

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000696 AC: 1018 AN: 1461856 Hom.: 1 Cov.: 33 AF XY: 0.000664 AC XY: 483 AN XY: 727234

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00191 AC: 102 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000782 AC: 870 AN: 1112006

Other (OTH) AF: 0.000613 AC: 37 AN: 60394

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74444

African (AFR) AF: 0.000168 AC: 7 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000576 Hom.: 0

Bravo AF: 0.000363

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000955 AC: 116

EpiCase AF: 0.000709

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	not provided (4)
1	2	-	Alpha-N-acetylgalactosaminidase deficiency type 1 (3)
-	1	-	Alpha-N-acetylgalactosaminidase deficiency (1)
-	1	-	Alpha-N-acetylgalactosaminidase deficiency type 2 (1)
1	-	-	Alpha-N-acetylgalactosaminidase deficiency type 3 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.25	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.71
Sift	Benign	0.17	T
Sift4G	Benign	0.064	T
Polyphen		0.10	B
Vest4		0.82
MVP		0.96
MPC		0.31
ClinPred		0.12	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.85
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs121434532; hg19: chr22-42463140; COSMIC: COSV67169893;