rs10444509

Variant names:

• chr12-101820252-T-C
• rs10444509
• NM_024312.5:c.117+10307A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024312.5(GNPTAB):​c.117+10307A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,204 control chromosomes in the GnomAD database, including 2,562 homozygotes. 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: 𝑓 0.18 (2562 hom., cov: 32)
• Consequence: GNPTAB NM_024312.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.578
• Publications: 9 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• mucolipidosis type III, alpha/beta

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.117+10307A>G		intron_variant	Intron 1 of 20	ENST00000299314.12	NP_077288.2
GNPTAB	XM_006719593.4	c.117+10307A>G		intron_variant	Intron 1 of 18		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.117+10307A>G		intron_variant	Intron 1 of 20	1	NM_024312.5	ENSP00000299314.7

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27454 AN: 152086 Hom.: 2562 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.164

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.180 AC: 27462 AN: 152204 Hom.: 2562 Cov.: 32 AF XY: 0.180 AC XY: 13420 AN XY: 74406

African (AFR) AF: 0.227 AC: 9416 AN: 41520

American (AMR) AF: 0.134 AC: 2049 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3472

East Asian (EAS) AF: 0.139 AC: 718 AN: 5178

South Asian (SAS) AF: 0.221 AC: 1068 AN: 4824

European-Finnish (FIN) AF: 0.169 AC: 1790 AN: 10596

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11418 AN: 68008

Other (OTH) AF: 0.170 AC: 358 AN: 2112

Alfa AF: 0.174 Hom.: 9371

Bravo AF: 0.178

Asia WGS AF: 0.193 AC: 669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.52
PhyloP100		0.58
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: rs10444509; hg19: chr12-102214030;