rs143788461

Variant names:

• chr12-101765157-C-G
• rs143788461
• NM_024312.5:c.1760G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-101765157-C-G
• chr12-101765157-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_024312.5(GNPTAB):​c.1760G>C​(p.Arg587Pro) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.29

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]

RNU6-101P (HGNC:47064): (RNA, U6 small nuclear 101, pseudogene)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 12-101765157-C-G is Pathogenic according to our data. Variant chr12-101765157-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551203.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}. Variant chr12-101765157-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.1760G>C	p.Arg587Pro	missense_variant	Exon 13 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.1679G>C	p.Arg560Pro	missense_variant	Exon 13 of 21		XP_011537033.1
GNPTAB	XM_006719593.4	c.1760G>C	p.Arg587Pro	missense_variant	Exon 13 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.1760G>C	p.Arg587Pro	missense_variant	Exon 13 of 21	1	NM_024312.5	ENSP00000299314.7
RNU6-101P	ENST00000410323.1	n.*249G>C		downstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucolipidosis Pathogenic:2

May 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GNPTAB c.1760G>C (p.Arg587Pro) results in a non-conservative amino acid change located in the spacer domain (Qian_2015) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251420 control chromosomes. c.1760G>C has been reported in the literature as a biallelic compound heterozygous genotype in at-least one individual affected with Mucolipidosis type IIIA with evidence of familial segregation (example: Lam_2007). These data indicate the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal phosphotransferase enzyme activity in-vitro (example: Qian_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26385638, 17034777, 25505245). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:1 Uncertain:1

Mar 21, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GNPTAB function (PMID: 25505245). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNPTAB protein function. ClinVar contains an entry for this variant (Variation ID: 551203). This missense change has been observed in individual(s) with clinical features of mucolipidosis IIIA (PMID: 17034777; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 587 of the GNPTAB protein (p.Arg587Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.85		Loss of MoRF binding (P = 0.0059);
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.92
gMVP		0.98

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: rs143788461; hg19: chr12-102158935;