rs139526942

Positions:

• chr16-5028124-G-A
• chr16-5028124-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_016256.4(NAGPA):​c.982C>T​(p.Arg328Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,603,088 control chromosomes in the GnomAD database, including 3 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 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: NAGPA NM_016256.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.984

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013908088).
• BP6: Variant 16-5028124-G-A is Benign according to our data. Variant chr16-5028124-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30694.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGPA	NM_016256.4	c.982C>T	p.Arg328Cys	missense_variant	6/10	ENST00000312251.8	NP_057340.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGPA	ENST00000312251.8	c.982C>T	p.Arg328Cys	missense_variant	6/10	1	NM_016256.4	ENSP00000310998	P1

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00105 AC: 237 AN: 224894 Hom.: 1 AF XY: 0.00114 AC XY: 139 AN XY: 122116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000627

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000583

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.000531 AC: 771 AN: 1450744 Hom.: 3 Cov.: 36 AF XY: 0.000553 AC XY: 399 AN XY: 720924

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000700

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74500

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00129 Hom.: 4

Bravo AF: 0.000654

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00117 AC: 10

ExAC AF: 0.000744 AC: 90

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NAGPA: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Stuttering, familial persistent, 2 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Nov 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.18
Sift	Benign	0.16	T;T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;.
Vest4		0.53
MVP		0.51
MPC		0.077
ClinPred		0.095	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.60

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: rs139526942; hg19: chr16-5078125;