12-64737039-G-C

Variant names:

• chr12-64737039-G-C
• NM_002076.4:c.1063C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002076.4(GNS):​c.1063C>G​(p.Arg355Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GNS NM_002076.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNS	NM_002076.4	c.1063C>G	p.Arg355Gly	missense_variant	Exon 9 of 14	ENST00000258145.8	NP_002067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNS	ENST00000258145.8	c.1063C>G	p.Arg355Gly	missense_variant	Exon 9 of 14	1	NM_002076.4	ENSP00000258145.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449104 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.7	.;H;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.86
MutPred		0.69		.;.;Gain of catalytic residue at L385 (P = 0);.;
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-65130819;