NM_002076.4:c.*2361C>G

Variant names:

• chr12-64714380-G-C
• rs1061743
• NM_002076.4:c.*2361C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002076.4(GNS):​c.*2361C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 151,998 control chromosomes in the GnomAD database, including 22,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22863 hom., cov: 32)
  • Exomes 𝑓: 0.69 (4 hom.)
• Consequence: GNS NM_002076.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.604
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-64714380-G-C is Benign according to our data. Variant chr12-64714380-G-C is described in ClinVar as Benign. ClinVar VariationId is 310175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.855 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.*2361C>G		3_prime_UTR	Exon 14 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.*2361C>G		3_prime_UTR	Exon 14 of 14	ENSP00000258145.3	P15586-1
	GNS	ENST00000418919.6	TSL:1	c.*2361C>G		3_prime_UTR	Exon 13 of 13	ENSP00000413130.2	H7C3P4
	GNS	ENST00000967913.1		c.*2361C>G		3_prime_UTR	Exon 14 of 14	ENSP00000637972.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81547 AN: 151864 Hom.: 22862 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.877

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.530

GnomAD4 exome AF: 0.688 AC: 11 AN: 16 Hom.: 4 Cov.: 0 AF XY: 0.750 AC XY: 9 AN XY: 12

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.875 AC: 7 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 3 AN: 4

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.537 AC: 81572 AN: 151982 Hom.: 22863 Cov.: 32 AF XY: 0.544 AC XY: 40370 AN XY: 74258

African (AFR) AF: 0.385 AC: 15937 AN: 41430

American (AMR) AF: 0.537 AC: 8211 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1590 AN: 3468

East Asian (EAS) AF: 0.876 AC: 4531 AN: 5172

South Asian (SAS) AF: 0.705 AC: 3404 AN: 4826

European-Finnish (FIN) AF: 0.626 AC: 6590 AN: 10534

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39602 AN: 67962

Other (OTH) AF: 0.535 AC: 1128 AN: 2108

Alfa AF: 0.552 Hom.: 2851

Bravo AF: 0.519

Asia WGS AF: 0.742 AC: 2581 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Mucopolysaccharidosis, MPS-III-D (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.60
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: rs1061743; hg19: chr12-65108160;