NM_024312.5:c.1042A>C

Variant names:

• chr12-101770477-T-G
• rs7958709
• NM_024312.5:c.1042A>C

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.1042A>C​(p.Ile348Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00213 in 1,613,892 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 5.84
• Publications: 12 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, Orphanet, Labcorp Genetics (formerly Invitae)
• mucolipidosis type III, alpha/beta

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009780139).
• BP6: Variant 12-101770477-T-G is Benign according to our data. Variant chr12-101770477-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39020.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 = 0.0117 (1781/152316) while in subpopulation AFR AF = 0.0411 (1707/41564). AF 95% confidence interval is 0.0394. There are 24 homozygotes in GnomAd4. There are 812 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.1042A>C	p.Ile348Leu	missense	Exon 9 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.1042A>C	p.Ile348Leu	missense	Exon 9 of 21	ENSP00000299314.7	Q3T906-1
	GNPTAB	ENST00000549940.5	TSL:1	c.1042A>C	p.Ile348Leu	missense	Exon 9 of 11	ENSP00000449150.1	Q3T906-2
	GNPTAB	ENST00000917136.1		c.1063A>C	p.Ile355Leu	missense	Exon 9 of 21	ENSP00000587195.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1783 AN: 152198 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

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: 0.0000294

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00302 AC: 759 AN: 251420 AF XY: 0.00216

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00113 AC: 1654 AN: 1461576 Hom.: 26 Cov.: 31 AF XY: 0.000989 AC XY: 719 AN XY: 727110

African (AFR) AF: 0.0416 AC: 1392 AN: 33460

American (AMR) AF: 0.00168 AC: 75 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111738

Other (OTH) AF: 0.00257 AC: 155 AN: 60380

GnomAD4 genome AF: 0.0117 AC: 1781 AN: 152316 Hom.: 24 Cov.: 32 AF XY: 0.0109 AC XY: 812 AN XY: 74484

African (AFR) AF: 0.0411 AC: 1707 AN: 41564

American (AMR) AF: 0.00386 AC: 59 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00415 Hom.: 38

Bravo AF: 0.0129

ESP6500AA AF: 0.0397 AC: 175

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00375 AC: 455

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Mucolipidosis type II (4)
-	-	3	not specified (3)
-	-	2	Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II (2)
-	-	1	Pseudo-Hurler polydystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.5	L
PhyloP100		5.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.012	D
Polyphen		0.90	P
Vest4		0.60
MVP		0.91
MPC		0.79
ClinPred		0.024	T
GERP RS		5.6
Varity_R		0.45
gMVP		0.79
Mutation Taster		=58/42	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

Other links and lift over

dbSNP: rs7958709; hg19: chr12-102164255;