rs386765812

Variant names:

• chr12-101764985-TG-CA
• rs386765812
• NM_024312.5:c.1931_1932delCAinsTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_024312.5(GNPTAB):​c.1931_1932delCAinsTG​(p.Thr644Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.0141 in 3,984 alleles, including 62 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T644I) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.014 Genomes: not found (cov: 32)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.46
• Publications: 4 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 -8 ACMG points.

• BP6: Variant 12-101764985-TG-CA is Benign according to our data. Variant chr12-101764985-TG-CA is described in ClinVar as [Likely_benign]. Clinvar id is 194266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.1931_1932delCAinsTG	p.Thr644Met	missense_variant		ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.1850_1851delCAinsTG	p.Thr617Met	missense_variant			XP_011537033.1
GNPTAB	XM_006719593.4	c.1931_1932delCAinsTG	p.Thr644Met	missense_variant			XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.1931_1932delCAinsTG	p.Thr644Met	missense_variant		1	NM_024312.5	ENSP00000299314.7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

GnomAD MNV AF: 0.0141 AC: 3984 Hom.: 62

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 18, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30548430, 25788519, 26130485, 30882951) -

Apr 27, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GNPTAB c.1931_1932delinsTG (p.Thr644delinsMet) variant involves the alteration a dinucleotide, resulting in a missense substitution that is not within a known functional domain (InterPro). 2/2 in silico tool predicts a damaging outcome for this variant (SNPs&GO was excluded due to a low reliability index and PolyPhen was unavailable during this analysis). This variant was found in 1646/122718 control chromosomes (24 homozygotes) at a frequency of 0.0134129, which is approximately 6 times the estimated maximal expected allele frequency of a pathogenic GNPTAB variant (0.0022361), suggesting this variant is likely a benign polymorphism. One clinical diagnostic laboratory has classified this variant as benign. In contrast, functional assays have suggested that protein function was partially impaired by the variant, which was identified in a mucolipidosis III patient in compound heterozygote state (Velho_2015, the other variant: c.3668_3670delCTA/T1223del). However, the patial loss of protein activity of GNPTAB-T644M in HEK-293 cells may not present in vivo or not be significant enough to cause disease. Taken together, this variant is classified as benign. -

not specified Benign:1

Sep 16, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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		3.5
Mutation Taster		=23/77	disease causing

Splicing

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

Other links and lift over

dbSNP: rs386765812; hg19: chr12-102158763;