chr12-64714380-G-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNS	NM_002076.4	c.*2361C>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000258145.8	NP_002067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNS	ENST00000258145	c.*2361C>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_002076.4	ENSP00000258145.3
GNS	ENST00000418919	c.*2361C>G		3_prime_UTR_variant	Exon 13 of 13	1		ENSP00000413130.2

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

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 0.875

Gnomad4 NFE exome AF: 0.750

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.537

Gnomad4 ASJ AF: 0.458

Gnomad4 EAS AF: 0.876

Gnomad4 SAS AF: 0.705

Gnomad4 FIN AF: 0.626

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.535

Alfa AF: 0.552 Hom.: 2851

Bravo AF: 0.519

Asia WGS AF: 0.742 AC: 2581 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-D Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.67

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

LitVar

Other links and lift over

dbSNP: rs1061743; hg19: chr12-65108160;