rs192687061

Positions:

• chr12-101761579-T-A
• chr12-101761579-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The ENST00000299314.12(GNPTAB):​c.2900A>T​(p.Gln967Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. Q967R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNPTAB ENST00000299314.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-101761579-T-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.2900A>T	p.Gln967Leu	missense_variant	14/21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.2819A>T	p.Gln940Leu	missense_variant	14/21		XP_011537033.1
GNPTAB	XM_006719593.4	c.2900A>T	p.Gln967Leu	missense_variant	14/19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.2900A>T	p.Gln967Leu	missense_variant	14/21	1	NM_024312.5	ENSP00000299314	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.71
Sift	Benign	0.094	T
Sift4G	Benign	0.80	T
Polyphen		1.0	D
Vest4		0.69
MutPred		0.35		Loss of disorder (P = 0.0756);
MVP		0.94
MPC		0.73
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.44
gMVP		0.77

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: rs192687061; hg19: chr12-102155357;