16-5028840-T-C

Variant names:

• chr16-5028840-T-C
• rs1995278
• NM_016256.4:c.920+40A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016256.4(NAGPA):​c.920+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,613,374 control chromosomes in the GnomAD database, including 806,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (76120 hom., cov: 33)
  • Exomes 𝑓: 1.0 (730424 hom.)
• Consequence: NAGPA NM_016256.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.291
• Publications: 7 publications found

Genes affected

NAGPA (HGNC:17378): (N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase) Hydrolases are transported to lysosomes after binding to mannose 6-phosphate receptors in the trans-Golgi network. This gene encodes the enzyme that catalyzes the second step in the formation of the mannose 6-phosphate recognition marker on lysosomal hydrolases. Commonly known as 'uncovering enzyme' or UCE, this enzyme removes N-acetyl-D-glucosamine (GlcNAc) residues from GlcNAc-alpha-P-mannose moieties and thereby produces the recognition marker. The encoded preproprotein is proteolytically processed by furin to generate the mature enzyme, a homotetramer of two disulfide-linked homodimers. Mutations in this gene are associated with developmental stuttering in human patients. [provided by RefSeq, Oct 2015]

ENSG00000267072 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-5028840-T-C is Benign according to our data. Variant chr16-5028840-T-C is described in ClinVar as Benign. ClinVar VariationId is 260708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016256.4. 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
	NAGPA	NM_016256.4	MANE Select	c.920+40A>G		intron	N/A	NP_057340.2	Q9UK23-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	ENST00000312251.8	TSL:1 MANE Select	c.920+40A>G		intron	N/A	ENSP00000310998.3	Q9UK23-1
	NAGPA	ENST00000948540.1		c.920+40A>G		intron	N/A	ENSP00000618599.1
	NAGPA	ENST00000948538.1		c.920+40A>G		intron	N/A	ENSP00000618597.1

Frequencies

GnomAD3 genomes AF: 1.00 AC: 152165 AN: 152208 Hom.: 76061 Cov.: 33

Gnomad AFR AF: 0.999

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 249703 AN: 249736 AF XY: 1.00

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1460948 AN: 1461048 Hom.: 730424 Cov.: 54 AF XY: 1.00 AC XY: 726798 AN XY: 726844

African (AFR) AF: 0.999 AC: 33459 AN: 33480

American (AMR) AF: 1.00 AC: 44708 AN: 44722

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39685 AN: 39698

South Asian (SAS) AF: 1.00 AC: 86243 AN: 86244

European-Finnish (FIN) AF: 1.00 AC: 52646 AN: 52646

Middle Eastern (MID) AF: 1.00 AC: 5767 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111924 AN: 1111966

Other (OTH) AF: 1.00 AC: 60380 AN: 60388

GnomAD4 genome AF: 1.00 AC: 152283 AN: 152326 Hom.: 76120 Cov.: 33 AF XY: 1.00 AC XY: 74455 AN XY: 74472

African (AFR) AF: 0.999 AC: 41538 AN: 41576

American (AMR) AF: 1.00 AC: 15301 AN: 15302

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5164

South Asian (SAS) AF: 1.00 AC: 4824 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10627 AN: 10628

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68042 AN: 68042

Other (OTH) AF: 1.00 AC: 2111 AN: 2112

Alfa AF: 1.00 Hom.: 13194

Bravo AF: 1.00

Asia WGS AF: 1.00 AC: 3478 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.43
PhyloP100		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs1995278; hg19: chr16-5078841;