rs74952829

Variant names:

• chr16-5033832-G-A
• rs74952829
• NM_016256.4:c.83C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-5033832-G-A
• chr16-5033832-G-C
• chr16-5033832-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016256.4(NAGPA):​c.83C>T​(p.Ser28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,551,882 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (21 hom.)
• Consequence: NAGPA NM_016256.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.458
• Publications: 2 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]

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]

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

ENSG00000267072 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026503801).
• BP6: Variant 16-5033832-G-A is Benign according to our data. Variant chr16-5033832-G-A is described in ClinVar as Benign. ClinVar VariationId is 717404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00874 (1331/152310) while in subpopulation AFR AF = 0.0307 (1278/41576). AF 95% confidence interval is 0.0293. There are 19 homozygotes in GnomAd4. There are 634 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.83C>T	p.Ser28Leu	missense	Exon 1 of 10	NP_057340.2	Q9UK23-1
	NAGPA-AS1	NR_038913.1		n.131G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	ENST00000312251.8	TSL:1 MANE Select	c.83C>T	p.Ser28Leu	missense	Exon 1 of 10	ENSP00000310998.3	Q9UK23-1
	NAGPA	ENST00000948540.1		c.83C>T	p.Ser28Leu	missense	Exon 1 of 11	ENSP00000618599.1
	NAGPA	ENST00000948538.1		c.83C>T	p.Ser28Leu	missense	Exon 1 of 10	ENSP00000618597.1

Frequencies

GnomAD3 genomes AF: 0.00873 AC: 1328 AN: 152192 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00201 AC: 311 AN: 154422 AF XY: 0.00161

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.000457

GnomAD4 exome AF: 0.000917 AC: 1283 AN: 1399572 Hom.: 21 Cov.: 34 AF XY: 0.000783 AC XY: 541 AN XY: 690572

African (AFR) AF: 0.0341 AC: 1084 AN: 31748

American (AMR) AF: 0.00120 AC: 43 AN: 35820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25196

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35922

South Asian (SAS) AF: 0.0000503 AC: 4 AN: 79562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48338

Middle Eastern (MID) AF: 0.000640 AC: 3 AN: 4686

European-Non Finnish (NFE) AF: 0.0000278 AC: 30 AN: 1080306

Other (OTH) AF: 0.00203 AC: 118 AN: 57994

GnomAD4 genome AF: 0.00874 AC: 1331 AN: 152310 Hom.: 19 Cov.: 32 AF XY: 0.00851 AC XY: 634 AN XY: 74478

African (AFR) AF: 0.0307 AC: 1278 AN: 41576

American (AMR) AF: 0.00216 AC: 33 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00334 Hom.: 13

Bravo AF: 0.00987

ESP6500AA AF: 0.0236 AC: 95

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00190 AC: 185

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.46
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.067
Sift	Benign	0.66	T
Sift4G	Benign	0.75	T
Polyphen		0.0010	B
Vest4		0.16
MVP		0.17
MPC		0.49
ClinPred		0.0080	T
GERP RS		-0.26
PromoterAI		-0.041	Neutral
Varity_R		0.040
gMVP		0.32
Mutation Taster		=99/1	polymorphism

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: rs74952829; hg19: chr16-5083833;