12-101770477-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024312.5(GNPTAB):​c.1042A>C​(p.Ile348Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00213 in 1,613,892 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 24 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 26 hom. )

Consequence

GNPTAB
NM_024312.5 missense

Scores

2
10
6

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 5.84
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009780139).
BP6
Variant 12-101770477-T-G is Benign according to our data. Variant chr12-101770477-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 39020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101770477-T-G is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1781/152316) while in subpopulation AFR AF= 0.0411 (1707/41564). AF 95% confidence interval is 0.0394. There are 24 homozygotes in gnomad4. There are 812 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GNPTABNM_024312.5 linkc.1042A>C p.Ile348Leu missense_variant 9/21 ENST00000299314.12 NP_077288.2 Q3T906-1
GNPTABXM_011538731.3 linkc.961A>C p.Ile321Leu missense_variant 9/21 XP_011537033.1
GNPTABXM_006719593.4 linkc.1042A>C p.Ile348Leu missense_variant 9/19 XP_006719656.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GNPTABENST00000299314.12 linkc.1042A>C p.Ile348Leu missense_variant 9/211 NM_024312.5 ENSP00000299314.7 Q3T906-1
GNPTABENST00000549940.5 linkc.1042A>C p.Ile348Leu missense_variant 9/111 ENSP00000449150.1 Q3T906-2

Frequencies

GnomAD3 genomes
AF:
0.0117
AC:
1783
AN:
152198
Hom.:
24
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0412
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00386
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00621
GnomAD3 exomes
AF:
0.00302
AC:
759
AN:
251420
Hom.:
8
AF XY:
0.00216
AC XY:
293
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.0425
Gnomad AMR exome
AF:
0.00162
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.00113
AC:
1654
AN:
1461576
Hom.:
26
Cov.:
31
AF XY:
0.000989
AC XY:
719
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.0416
Gnomad4 AMR exome
AF:
0.00168
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.00257
GnomAD4 genome
AF:
0.0117
AC:
1781
AN:
152316
Hom.:
24
Cov.:
32
AF XY:
0.0109
AC XY:
812
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.0411
Gnomad4 AMR
AF:
0.00386
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00614
Alfa
AF:
0.00245
Hom.:
16
Bravo
AF:
0.0129
ESP6500AA
AF:
0.0397
AC:
175
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00375
AC:
455
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 24, 2017- -
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicSep 27, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 24, 2019This variant is associated with the following publications: (PMID: 27884173, 19617216, 25505245, 22995991) -
Mucolipidosis type II Benign:3Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria providedclinical testingNatera, Inc.Jan 09, 2020- -
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
not specified Benign:3
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingAl Jalila Children’s Genomics Center, Al Jalila Childrens Speciality HospitalMar 25, 2020- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 10, 2021- -
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Benign:2
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 09, 2021- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Pseudo-Hurler polydystrophy Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.67
D;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D
MetaRNN
Benign
0.0098
T;T
MetaSVM
Uncertain
0.10
D
MutationAssessor
Benign
1.5
L;L
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-1.9
N;N
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0090
D;D
Sift4G
Uncertain
0.012
D;T
Polyphen
0.90
P;D
Vest4
0.60
MVP
0.91
MPC
0.79
ClinPred
0.024
T
GERP RS
5.6
Varity_R
0.45
gMVP
0.79

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7958709; hg19: chr12-102164255; API