rs751953529

Positions:

• chr12-101786012-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_024312.5(GNPTAB):​c.571G>A​(p.Val191Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000069 in 1,449,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V191V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GNPTAB NM_024312.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.61

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 8) in uniprot entity GNPTA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_024312.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-101786012-C-T is Pathogenic according to our data. Variant chr12-101786012-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397556.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-101786012-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTAB	NM_024312.5	c.571G>A	p.Val191Ile	missense_variant, splice_region_variant	5/21	ENST00000299314.12
GNPTAB	XM_011538731.3	c.490G>A	p.Val164Ile	missense_variant, splice_region_variant	5/21
GNPTAB	XM_006719593.4	c.571G>A	p.Val191Ile	missense_variant, splice_region_variant	5/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12	c.571G>A	p.Val191Ile	missense_variant, splice_region_variant	5/21	1	NM_024312.5	P1
GNPTAB	ENST00000549940.5	c.571G>A	p.Val191Ile	missense_variant, splice_region_variant	5/11	1
GNPTAB	ENST00000552681.1	c.205G>A	p.Val69Ile	missense_variant, splice_region_variant	1/3	1
GNPTAB	ENST00000550352.1	n.365G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250636 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449860 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 722134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

research

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Jan 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.60	N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.044	D;D;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.70	P;P;.
Vest4		0.20
MutPred		0.20		Loss of ubiquitination at K189 (P = 0.0954);Loss of ubiquitination at K189 (P = 0.0954);.;
MVP		0.86
MPC		0.24
ClinPred		0.56	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs751953529; hg19: chr12-102179790;