12-64752752-C-T

Variant names:

• chr12-64752752-C-T
• rs1147096
• NM_002076.4:c.198G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002076.4(GNS):​c.198G>A​(p.Pro66Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,443,948 control chromosomes in the GnomAD database, including 277,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P66P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.70 (38282 hom., cov: 32)
  • Exomes 𝑓: 0.60 (239134 hom.)
• Consequence: GNS NM_002076.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.442
• Publications: 24 publications found

Genes affected

GNS (HGNC:4422): (glucosamine (N-acetyl)-6-sulfatase) The product of this gene is a lysosomal enzyme found in all cells. It is involved in the catabolism of heparin, heparan sulphate, and keratan sulphate. Deficiency of this enzyme results in the accumulation of undegraded substrate and the lysosomal storage disorder mucopolysaccharidosis type IIID (Sanfilippo D syndrome). Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome. [provided by RefSeq, Jul 2008]

GNS Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 12-64752752-C-T is Benign according to our data. Variant chr12-64752752-C-T is described in ClinVar as Benign. ClinVar VariationId is 94029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.442 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002076.4. 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
	GNS	NM_002076.4	MANE Select	c.198G>A	p.Pro66Pro	synonymous	Exon 2 of 14	NP_002067.1	P15586-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNS	ENST00000258145.8	TSL:1 MANE Select	c.198G>A	p.Pro66Pro	synonymous	Exon 2 of 14	ENSP00000258145.3	P15586-1
	GNS	ENST00000418919.6	TSL:1	c.30G>A	p.Pro10Pro	synonymous	Exon 1 of 13	ENSP00000413130.2	H7C3P4
	GNS	ENST00000967913.1		c.312G>A	p.Pro104Pro	synonymous	Exon 2 of 14	ENSP00000637972.1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105697 AN: 152032 Hom.: 38235 Cov.: 32

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.661

GnomAD2 exomes AF: 0.641 AC: 157726 AN: 245972 AF XY: 0.638

Gnomad AFR exome AF: 0.912

Gnomad AMR exome AF: 0.565

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.878

Gnomad FIN exome AF: 0.636

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.602 AC: 777176 AN: 1291798 Hom.: 239134 Cov.: 22 AF XY: 0.604 AC XY: 393305 AN XY: 650962

African (AFR) AF: 0.908 AC: 26603 AN: 29290

American (AMR) AF: 0.571 AC: 25180 AN: 44112

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 12664 AN: 24888

East Asian (EAS) AF: 0.870 AC: 33728 AN: 38754

South Asian (SAS) AF: 0.662 AC: 54453 AN: 82290

European-Finnish (FIN) AF: 0.634 AC: 33597 AN: 52990

Middle Eastern (MID) AF: 0.573 AC: 3120 AN: 5444

European-Non Finnish (NFE) AF: 0.578 AC: 554185 AN: 959352

Other (OTH) AF: 0.615 AC: 33646 AN: 54678

GnomAD4 genome AF: 0.695 AC: 105795 AN: 152150 Hom.: 38282 Cov.: 32 AF XY: 0.696 AC XY: 51742 AN XY: 74372

African (AFR) AF: 0.904 AC: 37535 AN: 41534

American (AMR) AF: 0.618 AC: 9454 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1745 AN: 3470

East Asian (EAS) AF: 0.878 AC: 4545 AN: 5176

South Asian (SAS) AF: 0.679 AC: 3278 AN: 4826

European-Finnish (FIN) AF: 0.628 AC: 6639 AN: 10564

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40590 AN: 67976

Other (OTH) AF: 0.665 AC: 1405 AN: 2112

Alfa AF: 0.610 Hom.: 19483

Bravo AF: 0.700

Asia WGS AF: 0.773 AC: 2687 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Mucopolysaccharidosis, MPS-III-D (6)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Sanfilippo syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.7
DANN	Benign	0.48
PhyloP100		-0.44
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs1147096; hg19: chr12-65146532; COSMIC: COSV108044179;