12-64716806-G-C

Position:

chr12-64716806-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_002076.4(GNS):c.1594C>G(p.Pro532Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,610,962 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

GNS
NM_002076.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.46

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 links:

GNS (HGNC:):

GNS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21808535).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000432 (63/1458696) while in subpopulation MID AF= 0.000521 (3/5756). AF 95% confidence interval is 0.000224. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNS	NM_002076.4 linkuse as main transcript	c.1594C>G	p.Pro532Ala	missense_variant	14/14	ENST00000258145.8	NP_002067.1	P15586-1A0A024RBC5Q7Z3X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNS	ENST00000258145.8 linkuse as main transcript	c.1594C>G	p.Pro532Ala	missense_variant	14/14	1	NM_002076.4	ENSP00000258145.3		P15586-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000802

AC:

AN:

249228

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

134912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000717

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000432

AC:

AN:

1458696

Hom.:

Cov.:

AF XY:

0.0000510

AC XY:

AN XY:

725884

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000325

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000452

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-D

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 532 of the GNS protein (p.Pro532Ala). This variant is present in population databases (rs202228620, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with GNS-related conditions. ClinVar contains an entry for this variant (Variation ID: 598985). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	3billion	Sep 20, 2024	The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

Aggressive behavior;C0004352:Autism;C0018536:Hallux valgus;C0024421:Macroglossia;C0036572:Seizure;C0221354:Frontal bossing;C0240543:Bulbous nose;C0338656:Cognitive impairment;C0399526:Mandibular prognathia;C0557874:Global developmental delay;C1836195:Short toe;C1839739:Thick lower lip vermilion;C1844813:Widely spaced teeth;C1845847:Coarse facial features;C1846459:Slit-like opening of the exterior auditory meatus;C3161330:Intellectual disability, profound;C3553450:Profound global developmental delay;C3714756:Intellectual disability;C4023133:Shortening of all phalanges of fingers;C4024963:Abnormal aggressive, impulsive or violent behavior;C4025741:Clinodactyly of the 5th toe;C4551570:2-3 toe syndactyly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;T;T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.6

.;M;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.43

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.16

T;T;T;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.46, 0.87

.;P;P;.

Vest4

0.40

MutPred

0.56

.;.;Loss of disorder (P = 0.0162);.;

MVP

0.78

MPC

0.39

ClinPred

0.12

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over