dbSNP rs61745799: GNPTAB:p.Glu542Asp (chr12-101765291-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_024312.5(GNPTAB):c.1626A>T(p.Glu542Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,414 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E542?) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.76

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]

GNPTAB links:

RNU6-101P (HGNC:47064): (RNA, U6 small nuclear 101, pseudogene)

RNU6-101P links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a repeat LNR 2 (size 40) in uniprot entity GNPTA_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_024312.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-101765291-TTC-TG is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5 link	c.1626A>T	p.Glu542Asp	missense_variant	Exon 13 of 21	ENST00000299314.12	NP_077288.2	Q3T906-1
GNPTAB	XM_011538731.3 link	c.1545A>T	p.Glu515Asp	missense_variant	Exon 13 of 21		XP_011537033.1
GNPTAB	XM_006719593.4 link	c.1626A>T	p.Glu542Asp	missense_variant	Exon 13 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12 link	c.1626A>T	p.Glu542Asp	missense_variant	Exon 13 of 21	1	NM_024312.5	ENSP00000299314.7		Q3T906-1
RNU6-101P	ENST00000410323.1 link	n.*115A>T		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455414

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724488

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.0027

Eigen_PC

Benign

0.023

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.097

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.69

Sift

Benign

0.055

Sift4G

Benign

0.23

Polyphen

0.97

Vest4

0.54

MutPred

0.37

Gain of relative solvent accessibility (P = 0.0215);

MVP

0.94

MPC

0.61

ClinPred

0.92

GERP RS

2.4

Varity_R

0.16

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over