chr12-101746272-C-CCT

Variant names:

• chr12-101746272-C-CCT
• rs59855215
• NM_024312.5:c.*890_*891dupAG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_024312.5(GNPTAB):​c.*890_*891dupAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 152,240 control chromosomes in the GnomAD database, including 874 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.098 (873 hom., cov: 31)
  • Exomes 𝑓: 0.33 (1 hom.)
• Consequence: GNPTAB NM_024312.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.595
• Publications: 2 publications found

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]

GNPTAB Gene-Disease associations (from GenCC):

• GNPTAB-mucolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mucolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• mucolipidosis type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• mucolipidosis type III, alpha/beta

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-101746272-C-CCT is Benign according to our data. Variant chr12-101746272-C-CCT is described in ClinVar as [Likely_benign]. Clinvar id is 306778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.*890_*891dupAG		3_prime_UTR_variant	Exon 21 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.*890_*891dupAG		3_prime_UTR_variant	Exon 21 of 21		XP_011537033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.*890_*891dupAG		3_prime_UTR_variant	Exon 21 of 21	1	NM_024312.5	ENSP00000299314.7

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 14937 AN: 152116 Hom.: 872 Cov.: 31

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0844

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.333 AC: 2 AN: 6 Hom.: 1 Cov.: 0 AF XY: 0.333 AC XY: 2 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.333 AC: 2 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0981 AC: 14941 AN: 152234 Hom.: 873 Cov.: 31 AF XY: 0.0969 AC XY: 7215 AN XY: 74432

African (AFR) AF: 0.0348 AC: 1445 AN: 41552

American (AMR) AF: 0.139 AC: 2128 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3470

East Asian (EAS) AF: 0.172 AC: 890 AN: 5180

South Asian (SAS) AF: 0.0855 AC: 412 AN: 4820

European-Finnish (FIN) AF: 0.0873 AC: 926 AN: 10606

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8288 AN: 68000

Other (OTH) AF: 0.121 AC: 256 AN: 2110

Alfa AF: 0.112 Hom.: 132

Bravo AF: 0.103

Asia WGS AF: 0.109 AC: 378 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pseudo-Hurler polydystrophy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucolipidosis type II Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs59855215; hg19: chr12-102140050; COSMIC: COSV54776470; COSMIC: COSV54776470;