chr12-101765328-AT-A

Variant names:

• chr12-101765328-AT-A
• rs546802775
• NM_024312.5:c.1613-25delA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024312.5(GNPTAB):​c.1613-25delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,424,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (0 hom.)
• Consequence: GNPTAB NM_024312.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:2
• Conservation: PhyloP100: 0.155
• Publications: 0 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.0033) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	NM_024312.5	MANE Select	c.1613-25delA		intron	N/A	NP_077288.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	ENST00000299314.12	TSL:1 MANE Select	c.1613-25delA		intron	N/A	ENSP00000299314.7
	GNPTAB	ENST00000917136.1		c.1634-25delA		intron	N/A	ENSP00000587195.1
	GNPTAB	ENST00000917134.1		c.1607-25delA		intron	N/A	ENSP00000587193.1

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150380 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000980

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000487

GnomAD2 exomes AF: 0.00181 AC: 352 AN: 194538 AF XY: 0.00170

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00185

Gnomad EAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00230

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.00153

GnomAD4 exome AF: 0.00298 AC: 3801 AN: 1273696 Hom.: 0 Cov.: 20 AF XY: 0.00277 AC XY: 1768 AN XY: 638672

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00297 AC: 87 AN: 29298

American (AMR) AF: 0.00170 AC: 70 AN: 41174

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 37 AN: 23492

East Asian (EAS) AF: 0.000601 AC: 22 AN: 36610

South Asian (SAS) AF: 0.00192 AC: 150 AN: 78016

European-Finnish (FIN) AF: 0.00123 AC: 61 AN: 49484

Middle Eastern (MID) AF: 0.00150 AC: 8 AN: 5326

European-Non Finnish (NFE) AF: 0.00339 AC: 3248 AN: 957032

Other (OTH) AF: 0.00222 AC: 118 AN: 53264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150380 Hom.: 0 Cov.: 33 AF XY: 0.0000273 AC XY: 2 AN XY: 73284

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000489 AC: 2 AN: 40938

American (AMR) AF: 0.00 AC: 0 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.0000980 AC: 1 AN: 10208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67494

Other (OTH) AF: 0.000487 AC: 1 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00749685), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00852 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15

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: rs546802775; hg19: chr12-102159106; COSMIC: COSV54777349; COSMIC: COSV54777349;