rs119461974

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_002076.4(GNS):c.1063C>T(p.Arg355*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,449,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GNS
NM_002076.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.55

Publications

16 publications found

Variant links:

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

GNS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-64737039-G-A is Pathogenic according to our data. Variant chr12-64737039-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNS	NM_002076.4	MANE Select	c.1063C>T	p.Arg355*	stop_gained	Exon 9 of 14	NP_002067.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNS	ENST00000258145.8	TSL:1 MANE Select	c.1063C>T	p.Arg355*	stop_gained	Exon 9 of 14	ENSP00000258145.3
GNS	ENST00000418919.6	TSL:1	c.895C>T	p.Arg299*	stop_gained	Exon 8 of 13	ENSP00000413130.2
GNS	ENST00000543646.5	TSL:2	c.1159C>T	p.Arg387*	stop_gained	Exon 10 of 15	ENSP00000438497.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251476

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000621

AC:

AN:

1449102

Hom.:

Cov.:

AF XY:

0.00000831

AC XY:

AN XY:

721844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33196

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39634

South Asian (SAS)

AF:

0.0000582

AC:

AN:

85966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1100400

Other (OTH)

AF:

0.00

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-D

Pathogenic:3

May 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg355*) in the GNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNS are known to be pathogenic (PMID: 20232353). This variant is present in population databases (rs119461974, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 12573255). ClinVar contains an entry for this variant (Variation ID: 2932). For these reasons, this variant has been classified as Pathogenic.

not provided

Pathogenic:1

Jan 11, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Multiple functional studies performed using patient-derived cell lines demonstrated no N-acetylglucosamine 6-sulfatase activity in cells homozygous for this variant (Pierzynowska et al., 2020; Wang et al., 2021; Gaffke et al., 2022); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32944950, 12573255, 34928474, 33195185, 33320673, 32366041, 34828358)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.95

PhyloP100

2.6

Vest4

0.98

ClinPred

1.0

GERP RS

5.5

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over