rs281865002

chr12-101761702-T-Achr12-101761702-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_024312.5(GNPTAB):c.2777A>T(p.Gln926Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q926P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-101761702-T-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.39332324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTAB	NM_024312.5	c.2777A>T	p.Gln926Leu	missense_variant	14/21	ENST00000299314.12
GNPTAB	XM_011538731.3	c.2696A>T	p.Gln899Leu	missense_variant	14/21
GNPTAB	XM_006719593.4	c.2777A>T	p.Gln926Leu	missense_variant	14/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12	c.2777A>T	p.Gln926Leu	missense_variant	14/21	1	NM_024312.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.0053
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.024	D
Polyphen		0.51	P
Vest4		0.52
MutPred		0.23		Loss of methylation at K921 (P = 0.044);
MVP		0.89
MPC		0.25
ClinPred		0.88	D
GERP RS		4.7
Varity_R		0.24
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs281865002; hg19: chr12-102155480;