NM_024312.5:c.3336-25T>C

Variant names:

• chr12-101757335-A-G
• rs3736476
• NM_024312.5:c.3336-25T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024312.5(GNPTAB):​c.3336-25T>C variant causes a intron change. The variant allele was found at a frequency of 0.304 in 1,299,802 control chromosomes in the GnomAD database, including 61,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7344 hom., cov: 32)
  • Exomes 𝑓: 0.30 (53853 hom.)
• Consequence: GNPTAB NM_024312.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.01
• Publications: 7 publications found

Genes affected

GNPTAB (HGNC:29670): (N-acetylglucosamine-1-phosphate transferase subunits alpha and beta) This gene encodes two of three subunit types of the membrane-bound enzyme N-acetylglucosamine-1-phosphotransferase, a heterohexameric complex composed of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved at the Lys928-Asp929 bond to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GeneID 84572). In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for appropriate trafficking of lysosomal enzymes. Mutations in this gene have been associated with both mucolipidosis II and mucolipidosis IIIA.[provided by RefSeq, May 2010]

GNPTAB Gene-Disease associations (from GenCC):

• GNPTAB-mucolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mucolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• mucolipidosis type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• mucolipidosis type III, alpha/beta

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-101757335-A-G is Benign according to our data. Variant chr12-101757335-A-G is described in ClinVar as Benign. ClinVar VariationId is 261695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024312.5. 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
	GNPTAB	NM_024312.5	MANE Select	c.3336-25T>C		intron	N/A	NP_077288.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	ENST00000299314.12	TSL:1 MANE Select	c.3336-25T>C		intron	N/A	ENSP00000299314.7	Q3T906-1
	GNPTAB	ENST00000917136.1		c.3357-25T>C		intron	N/A	ENSP00000587195.1
	GNPTAB	ENST00000917134.1		c.3330-25T>C		intron	N/A	ENSP00000587193.1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46867 AN: 151780 Hom.: 7344 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.297

GnomAD2 exomes AF: 0.320 AC: 76594 AN: 239228 AF XY: 0.316

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.395

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.303 AC: 348234 AN: 1147900 Hom.: 53853 Cov.: 15 AF XY: 0.301 AC XY: 176372 AN XY: 584998

African (AFR) AF: 0.284 AC: 7598 AN: 26754

American (AMR) AF: 0.337 AC: 14338 AN: 42540

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 7819 AN: 23942

East Asian (EAS) AF: 0.374 AC: 14255 AN: 38066

South Asian (SAS) AF: 0.238 AC: 18282 AN: 76810

European-Finnish (FIN) AF: 0.421 AC: 22246 AN: 52834

Middle Eastern (MID) AF: 0.284 AC: 1411 AN: 4964

European-Non Finnish (NFE) AF: 0.297 AC: 246766 AN: 832208

Other (OTH) AF: 0.312 AC: 15519 AN: 49782

GnomAD4 genome AF: 0.309 AC: 46907 AN: 151902 Hom.: 7344 Cov.: 32 AF XY: 0.312 AC XY: 23178 AN XY: 74254

African (AFR) AF: 0.286 AC: 11812 AN: 41312

American (AMR) AF: 0.308 AC: 4704 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1102 AN: 3472

East Asian (EAS) AF: 0.393 AC: 2036 AN: 5184

South Asian (SAS) AF: 0.233 AC: 1121 AN: 4820

European-Finnish (FIN) AF: 0.443 AC: 4677 AN: 10550

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20498 AN: 67984

Other (OTH) AF: 0.296 AC: 625 AN: 2108

Alfa AF: 0.301 Hom.: 2826

Bravo AF: 0.298

Asia WGS AF: 0.335 AC: 1162 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Mucolipidosis type II (1)
-	-	1	not specified (1)
-	-	1	Pseudo-Hurler polydystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.81
PhyloP100		4.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs3736476; hg19: chr12-102151113; COSMIC: COSV73418404;