16-5027156-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_016256.4(NAGPA):c.1319G>C(p.Gly440Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,614,238 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (4 hom.)
• Consequence: NAGPA NM_016256.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0850

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074922144).
• BP6: Variant 16-5027156-C-G is Benign according to our data. Variant chr16-5027156-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3041527.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGPA	NM_016256.4	c.1319G>C	p.Gly440Ala	missense_variant	9/10	ENST00000312251.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGPA	ENST00000312251.8	c.1319G>C	p.Gly440Ala	missense_variant	9/10	1	NM_016256.4	P1

Frequencies

GnomAD3 genomes AF: 0.000617 AC: 94 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.000843 AC: 212 AN: 251452 Hom.: 1 AF XY: 0.000920 AC XY: 125 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000862

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000647 AC: 946 AN: 1461882 Hom.: 4 Cov.: 32 AF XY: 0.000672 AC XY: 489 AN XY: 727244

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000563

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74496

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000835 Hom.: 0

Bravo AF: 0.000903

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000923 AC: 112

EpiCase AF: 0.00125

EpiControl AF: 0.00142

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NAGPA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.67
Dann	Benign	0.57
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.071
Sift	Benign	0.27	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.16	B;.
Vest4		0.28
MVP		0.20
MPC		0.017
ClinPred		0.018	T
GERP RS		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149923128; hg19: chr16-5077157;