12-101796744-G-T

Variant names:

• chr12-101796744-G-T
• rs78347057
• NM_024312.5:c.136C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024312.5(GNPTAB):​c.136C>A​(p.Arg46Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,611,930 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (19 hom.)
• Consequence: GNPTAB NM_024312.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.93
• Publications: 6 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]

RNU6-172P (HGNC:47135): (RNA, U6 small nuclear 172, pseudogene)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-101796744-G-T is Benign according to our data. Variant chr12-101796744-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00943 (1434/152016) while in subpopulation AFR AF = 0.0327 (1355/41462). AF 95% confidence interval is 0.0312. There are 26 homozygotes in GnomAd4. There are 669 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.136C>A	p.Arg46Arg	synonymous	Exon 2 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.136C>A	p.Arg46Arg	synonymous	Exon 2 of 21	ENSP00000299314.7
	GNPTAB	ENST00000549940.5	TSL:1	c.136C>A	p.Arg46Arg	synonymous	Exon 2 of 11	ENSP00000449150.1
	GNPTAB	ENST00000392919.4	TSL:1	c.136C>A	p.Arg46Arg	synonymous	Exon 2 of 3	ENSP00000376651.4

Frequencies

GnomAD3 genomes AF: 0.00939 AC: 1427 AN: 151898 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

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: 0.00913

GnomAD2 exomes AF: 0.00263 AC: 660 AN: 251002 AF XY: 0.00197

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000904 AC: 1320 AN: 1459914 Hom.: 19 Cov.: 29 AF XY: 0.000760 AC XY: 552 AN XY: 726426

African (AFR) AF: 0.0309 AC: 1032 AN: 33384

American (AMR) AF: 0.00210 AC: 94 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1110604

Other (OTH) AF: 0.00264 AC: 159 AN: 60328

GnomAD4 genome AF: 0.00943 AC: 1434 AN: 152016 Hom.: 26 Cov.: 32 AF XY: 0.00901 AC XY: 669 AN XY: 74286

African (AFR) AF: 0.0327 AC: 1355 AN: 41462

American (AMR) AF: 0.00367 AC: 56 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67972

Other (OTH) AF: 0.00903 AC: 19 AN: 2104

Alfa AF: 0.00335 Hom.: 5

Bravo AF: 0.0112

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Mucolipidosis type II (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
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.5
DANN	Benign	0.78
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs78347057; hg19: chr12-102190522;