chr16-5027394-TGGGAGGA-T

Position:

• chr16-5027394-TGGGAGGA-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_016256.4(NAGPA):​c.1175-22_1175-16del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,608,326 control chromosomes in the GnomAD database, including 138,732 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (11732 hom., cov: 0)
  • Exomes 𝑓: 0.41 (127000 hom.)
• Consequence: NAGPA NM_016256.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.20

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 -10 ACMG points.

• BP6: Variant 16-5027394-TGGGAGGA-T is Benign according to our data. Variant chr16-5027394-TGGGAGGA-T is described in ClinVar as [Likely_benign]. Clinvar id is 260703.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGPA	NM_016256.4	c.1175-22_1175-16del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000312251.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGPA	ENST00000312251.8	c.1175-22_1175-16del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_016256.4	P1

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59455 AN: 151294 Hom.: 11716 Cov.: 0

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.428

GnomAD3 exomes AF: 0.382 AC: 94151 AN: 246258 Hom.: 18337 AF XY: 0.392 AC XY: 52433 AN XY: 133880

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.345

Gnomad SAS exome AF: 0.412

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.413

GnomAD4 exome AF: 0.414 AC: 603491 AN: 1456908 Hom.: 127000 AF XY: 0.416 AC XY: 301830 AN XY: 724976

Gnomad4 AFR exome AF: 0.371

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.416

Gnomad4 FIN exome AF: 0.353

Gnomad4 NFE exome AF: 0.424

Gnomad4 OTH exome AF: 0.421

GnomAD4 genome AF: 0.393 AC: 59505 AN: 151418 Hom.: 11732 Cov.: 0 AF XY: 0.389 AC XY: 28763 AN XY: 73956

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.448

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.424

Gnomad4 OTH AF: 0.423

Alfa AF: 0.304 Hom.: 1185

Bravo AF: 0.393

Asia WGS AF: 0.323 AC: 1123 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs71402581; hg19: chr16-5077395;