rs386765812

chr12-101764985-TG-CA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PS1_Moderate PM2 BP6_Very_Strong

The NM_024312.5(GNPTAB):c.1931_1932inv(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. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T644I) has been classified as Likely benign.

• Frequency: 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

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 Likely_benign. Variant got -4 ACMG points.

• PS1: Transcript NM_024312.5 (GNPTAB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• 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/exons	MANE	UniProt
GNPTAB	NM_024312.5	c.1931_1932inv	p.Thr644Met	missense_variant	13/21	ENST00000299314.12
GNPTAB	XM_006719593.4	c.1931_1932inv	p.Thr644Met	missense_variant	13/19
GNPTAB	XM_011538731.3	c.1850_1851inv	p.Thr617Met	missense_variant	13/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12	c.1931_1932inv	p.Thr644Met	missense_variant	13/21	1	NM_024312.5	P1

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

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2019	This variant is associated with the following publications: (PMID: 30548430, 25788519, 26130485, 30882951) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 16, 2014

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs386765812; hg19: chr12-102158763;