chr22-42058583-G-A

Position:

• chr22-42058583-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000262.3(NAGA):​c.*1696C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 152,258 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAGA NM_000262.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.45

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 22-42058583-G-A is Benign according to our data. Variant chr22-42058583-G-A is described in ClinVar as [Benign]. Clinvar id is 341889.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0112 (1699/152258) while in subpopulation SAS AF= 0.0313 (151/4820). AF 95% confidence interval is 0.0273. There are 22 homozygotes in gnomad4. There are 851 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGA	NM_000262.3	c.*1696C>T		3_prime_UTR_variant	9/9	ENST00000396398.8	NP_000253.1
NAGA	NM_001362848.1	c.*1696C>T		3_prime_UTR_variant	10/10		NP_001349777.1
NAGA	NM_001362850.1	c.*1696C>T		3_prime_UTR_variant	10/10		NP_001349779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGA	ENST00000396398.8	c.*1696C>T		3_prime_UTR_variant	9/9	1	NM_000262.3	ENSP00000379680	P1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1700 AN: 152140 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.0186

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0115

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0112 AC: 1699 AN: 152258 Hom.: 22 Cov.: 32 AF XY: 0.0114 AC XY: 851 AN XY: 74450

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0118 Hom.: 3

Bravo AF: 0.0107

Asia WGS AF: 0.0250 AC: 86 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	0.95
DANN	Benign	0.57

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: rs11703233; hg19: chr22-42454587;