rs56212569

Variant names:

• chr12-101764306-C-T
• rs56212569
• NM_024312.5:c.2611G>A
• GNPTAB p.Gly871Ser

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024312.5(GNPTAB):​c.2611G>A​(p.Gly871Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,613,954 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G871G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (31 hom.)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0540
• Publications: 9 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• mucolipidosis type III, alpha/beta

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00276044).
• BP6: Variant 12-101764306-C-T is Benign according to our data. Variant chr12-101764306-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1711/152288) while in subpopulation AFR AF = 0.0389 (1615/41538). AF 95% confidence interval is 0.0373. There are 41 homozygotes in GnomAd4. There are 815 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024312.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	NM_024312.5	MANE Select	c.2611G>A	p.Gly871Ser	missense	Exon 13 of 21	NP_077288.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	ENST00000299314.12	TSL:1 MANE Select	c.2611G>A	p.Gly871Ser	missense	Exon 13 of 21	ENSP00000299314.7	Q3T906-1
	GNPTAB	ENST00000917136.1		c.2632G>A	p.Gly878Ser	missense	Exon 13 of 21	ENSP00000587195.1
	GNPTAB	ENST00000917134.1		c.2605G>A	p.Gly869Ser	missense	Exon 13 of 21	ENSP00000587193.1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1698 AN: 152170 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00310 AC: 778 AN: 251246 AF XY: 0.00233

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00108 AC: 1585 AN: 1461666 Hom.: 31 Cov.: 33 AF XY: 0.000909 AC XY: 661 AN XY: 727160

African (AFR) AF: 0.0375 AC: 1253 AN: 33430

American (AMR) AF: 0.00255 AC: 114 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111956

Other (OTH) AF: 0.00296 AC: 179 AN: 60388

GnomAD4 genome AF: 0.0112 AC: 1711 AN: 152288 Hom.: 41 Cov.: 33 AF XY: 0.0109 AC XY: 815 AN XY: 74472

African (AFR) AF: 0.0389 AC: 1615 AN: 41538

American (AMR) AF: 0.00457 AC: 70 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00453 Hom.: 28

Bravo AF: 0.0132

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Mucolipidosis type II (2)
-	-	2	not specified (2)
-	-	1	Pseudo-Hurler polydystrophy (1)
-	-	1	Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.4
DANN	Benign	0.42
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.054
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.17
Sift	Benign	0.72	T
Sift4G	Benign	0.71	T
Varity_R		0.020
gMVP		0.36
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56212569;

hg19: chr12-102158084;

COSMIC: COSV99076108;

COSMIC: COSV99076108;