Genetic Variant NM_016256.4:c.252C>T (chr16-5033563-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016256.4(NAGPA):c.252C>T(p.His84His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000813 in 1,353,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000081 ( 0 hom. )

Consequence

NAGPA
NM_016256.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.03

Publications

0 publications found

Variant links:

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]

NAGPA links:

ENSG00000267072 (HGNC:):

ENSG00000267072 links:

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ALG1 links:

NAGPA-AS1 (HGNC:44184): (NAGPA antisense RNA 1)

NAGPA-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGPA	NM_016256.4 link	c.252C>T	p.His84His	synonymous_variant	Exon 2 of 10	ENST00000312251.8	NP_057340.2
NAGPA-AS1	NR_038913.1 link	n.-139G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGPA	ENST00000312251.8 link	c.252C>T	p.His84His	synonymous_variant	Exon 2 of 10	1	NM_016256.4	ENSP00000310998.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000813

AC:

AN:

1353642

Hom.:

Cov.:

AF XY:

0.00000599

AC XY:

AN XY:

667270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28426

American (AMR)

AF:

0.00

AC:

AN:

29544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23458

East Asian (EAS)

AF:

0.00

AC:

AN:

33716

South Asian (SAS)

AF:

0.00

AC:

AN:

75820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4036

European-Non Finnish (NFE)

AF:

0.0000103

AC:

AN:

1068880

Other (OTH)

AF:

0.00

AC:

AN:

56150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

1.0

PromoterAI

0.088

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over