chr12-101765328-A-AT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The ENST00000299314.12(GNPTAB):​c.1613-25_1613-24insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,435,622 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (15 hom.)
• Consequence: GNPTAB ENST00000299314.12 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 12-101765328-A-AT is Benign according to our data. Variant chr12-101765328-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 558794.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000299314.12. 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.1613-25dupA		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.1613-25_1613-24insA		intron	N/A	ENSP00000299314.7
	RNU6-101P	ENST00000410323.1	TSL:6	n.*77_*78insA		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 403 AN: 150402 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000708

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00168

Gnomad FIN AF: 0.00617

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00418

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.00448 AC: 872 AN: 194538 AF XY: 0.00432

Gnomad AFR exome AF: 0.000850

Gnomad AMR exome AF: 0.000554

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.00103

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.00623

Gnomad OTH exome AF: 0.00437

GnomAD4 exome AF: 0.00508 AC: 6529 AN: 1285110 Hom.: 15 Cov.: 20 AF XY: 0.00487 AC XY: 3140 AN XY: 644550

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

African (AFR) AF: 0.00196 AC: 58 AN: 29554

American (AMR) AF: 0.000479 AC: 20 AN: 41786

Ashkenazi Jewish (ASJ) AF: 0.000839 AC: 20 AN: 23840

East Asian (EAS) AF: 0.00105 AC: 39 AN: 37052

South Asian (SAS) AF: 0.00163 AC: 129 AN: 78982

European-Finnish (FIN) AF: 0.00984 AC: 492 AN: 49988

Middle Eastern (MID) AF: 0.00168 AC: 9 AN: 5372

European-Non Finnish (NFE) AF: 0.00579 AC: 5582 AN: 964776

Other (OTH) AF: 0.00335 AC: 180 AN: 53760

⚠️ 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: 0.00266 AC: 401 AN: 150512 Hom.: 2 Cov.: 33 AF XY: 0.00272 AC XY: 200 AN XY: 73416

African (AFR) AF: 0.000706 AC: 29 AN: 41060

American (AMR) AF: 0.000662 AC: 10 AN: 15112

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

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5156

South Asian (SAS) AF: 0.00168 AC: 8 AN: 4750

European-Finnish (FIN) AF: 0.00617 AC: 63 AN: 10212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00416 AC: 281 AN: 67498

Other (OTH) AF: 0.000963 AC: 2 AN: 2076

Alfa AF: 0.00433 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs546802775; hg19: chr12-102159106;