chr12-64758386-G-A

Variant names:

• chr12-64758386-G-A
• rs1147091
• NM_002076.4:c.192+699C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002076.4(GNS):​c.192+699C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 143,634 control chromosomes in the GnomAD database, including 22,135 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (22135 hom., cov: 21)
• Consequence: GNS NM_002076.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75
• Publications: 4 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: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNS	NM_002076.4	c.192+699C>T		intron_variant	Intron 1 of 13	ENST00000258145.8	NP_002067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNS	ENST00000258145.8	c.192+699C>T		intron_variant	Intron 1 of 13	1	NM_002076.4	ENSP00000258145.3
GNS	ENST00000543646.5	c.192+699C>T		intron_variant	Intron 1 of 14	2		ENSP00000438497.1
GNS	ENST00000542058.5	c.192+699C>T		intron_variant	Intron 1 of 12	2		ENSP00000444819.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 78720 AN: 143542 Hom.: 22132 Cov.: 21

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.477

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.542

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.548 AC: 78744 AN: 143634 Hom.: 22135 Cov.: 21 AF XY: 0.553 AC XY: 38382 AN XY: 69418

African (AFR) AF: 0.407 AC: 15352 AN: 37702

American (AMR) AF: 0.551 AC: 7771 AN: 14094

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1581 AN: 3432

East Asian (EAS) AF: 0.879 AC: 4334 AN: 4930

South Asian (SAS) AF: 0.679 AC: 3056 AN: 4498

European-Finnish (FIN) AF: 0.640 AC: 5766 AN: 9004

Middle Eastern (MID) AF: 0.475 AC: 133 AN: 280

European-Non Finnish (NFE) AF: 0.587 AC: 39238 AN: 66832

Other (OTH) AF: 0.547 AC: 1076 AN: 1966

Alfa AF: 0.554 Hom.: 3105

Bravo AF: 0.522

Asia WGS AF: 0.734 AC: 2553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.69
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs1147091; hg19: chr12-65152166;