rs79493678

Variant names:

• chr12-101753364-G-T
• rs79493678
• NM_024312.5:c.3602+8C>A

Variant summary

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

The NM_024312.5(GNPTAB):​c.3602+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,608,380 control chromosomes in the GnomAD database, including 1,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (90 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1322 hom.)
• Consequence: GNPTAB NM_024312.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003069
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.346
• Publications: 11 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=-0.8).
• BP6: Variant 12-101753364-G-T is Benign according to our data. Variant chr12-101753364-G-T is described in ClinVar as Benign. ClinVar VariationId is 96122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0288 (4375/151848) while in subpopulation NFE AF = 0.0461 (3136/68000). AF 95% confidence interval is 0.0448. There are 90 homozygotes in GnomAd4. There are 2068 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 90 AR gene

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.3602+8C>A		splice_region 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.3602+8C>A		splice_region intron	N/A	ENSP00000299314.7	Q3T906-1
	GNPTAB	ENST00000917136.1		c.3623+8C>A		splice_region intron	N/A	ENSP00000587195.1
	GNPTAB	ENST00000917134.1		c.3596+8C>A		splice_region intron	N/A	ENSP00000587193.1

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4378 AN: 151728 Hom.: 90 Cov.: 33

Gnomad AFR AF: 0.00652

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.0325 AC: 8157 AN: 251282 AF XY: 0.0327

Gnomad AFR exome AF: 0.00674

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0491

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0368

GnomAD4 exome AF: 0.0392 AC: 57109 AN: 1456532 Hom.: 1322 Cov.: 30 AF XY: 0.0384 AC XY: 27853 AN XY: 724966

African (AFR) AF: 0.00579 AC: 192 AN: 33144

American (AMR) AF: 0.0177 AC: 789 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 706 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39646

South Asian (SAS) AF: 0.00547 AC: 471 AN: 86150

European-Finnish (FIN) AF: 0.0493 AC: 2634 AN: 53400

Middle Eastern (MID) AF: 0.0335 AC: 193 AN: 5754

European-Non Finnish (NFE) AF: 0.0454 AC: 50252 AN: 1107464

Other (OTH) AF: 0.0311 AC: 1871 AN: 60190

GnomAD4 genome AF: 0.0288 AC: 4375 AN: 151848 Hom.: 90 Cov.: 33 AF XY: 0.0279 AC XY: 2068 AN XY: 74250

African (AFR) AF: 0.00648 AC: 267 AN: 41220

American (AMR) AF: 0.0178 AC: 272 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.0448 AC: 473 AN: 10560

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0461 AC: 3136 AN: 68000

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0391 Hom.: 65

Bravo AF: 0.0261

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0420

EpiControl AF: 0.0438

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Mucolipidosis type II (3)
-	-	3	not specified (3)
-	-	2	Pseudo-Hurler polydystrophy (2)
-	-	1	Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.44
DANN	Benign	0.51
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.054
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: rs79493678; hg19: chr12-102147142; COSMIC: COSV107340415; COSMIC: COSV107340415;