rs281865010

Variant names:

• chr12-101760119-G-C
• rs281865010
• NM_024312.5:c.3160C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024312.5(GNPTAB):​c.3160C>G​(p.Leu1054Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.842

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.3160C>G	p.Leu1054Val	missense_variant	Exon 16 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.3079C>G	p.Leu1027Val	missense_variant	Exon 16 of 21		XP_011537033.1
GNPTAB	XM_006719593.4	c.3160C>G	p.Leu1054Val	missense_variant	Exon 16 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.3160C>G	p.Leu1054Val	missense_variant	Exon 16 of 21	1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000549194.1	n.26C>G		non_coding_transcript_exon_variant	Exon 1 of 3	3
GNPTAB	ENST00000550718.1	c.-30C>G		upstream_gene_variant		3		ENSP00000449557.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457138 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725200

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Mucolipidosis type II Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.033
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.22		Loss of helix (P = 0.0167);
MVP		0.74
MPC		0.71
ClinPred		0.80	D
GERP RS		0.81
Varity_R		0.26
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs281865010; hg19: chr12-102153897;