rs151013014

Variant names:

• chr17-42543866-C-T
• rs151013014
• NM_000263.4:c.1860C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-42543866-C-T
• chr17-42543866-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000263.4(NAGLU):​c.1860C>T​(p.Ser620Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,603,066 control chromosomes in the GnomAD database, including 13 homozygotes. 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 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: NAGLU NM_000263.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.476
• Publications: 1 publications found

Genes affected

NAGLU (HGNC:7632): (N-acetyl-alpha-glucosaminidase) This gene encodes an enzyme that degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides. Defects in this gene are the cause of mucopolysaccharidosis type IIIB (MPS-IIIB), also known as Sanfilippo syndrome B. This disease is characterized by the lysosomal accumulation and urinary excretion of heparan sulfate. [provided by RefSeq, Jul 2008]

NAGLU Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Myriad Women’s Health, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease axonal type 2V

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000266929 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 17-42543866-C-T is Benign according to our data. Variant chr17-42543866-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 323304.
• BP7: Synonymous conserved (PhyloP=0.476 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00175 (267/152344) while in subpopulation NFE AF = 0.00341 (232/68028). AF 95% confidence interval is 0.00305. There are 1 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000263.4. 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
	NAGLU	NM_000263.4	MANE Select	c.1860C>T	p.Ser620Ser	synonymous	Exon 6 of 6	NP_000254.2	A0A140VJE4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	ENST00000225927.7	TSL:1 MANE Select	c.1860C>T	p.Ser620Ser	synonymous	Exon 6 of 6	ENSP00000225927.1	P54802
	NAGLU	ENST00000963429.1		c.1938C>T	p.Ser646Ser	synonymous	Exon 6 of 6	ENSP00000633488.1
	NAGLU	ENST00000904921.1		c.1917C>T	p.Ser639Ser	synonymous	Exon 7 of 7	ENSP00000574980.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 267 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00168 AC: 381 AN: 227436 AF XY: 0.00161

Gnomad AFR exome AF: 0.000361

Gnomad AMR exome AF: 0.000466

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000576

Gnomad NFE exome AF: 0.00323

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00316 AC: 4584 AN: 1450722 Hom.: 12 Cov.: 32 AF XY: 0.00303 AC XY: 2186 AN XY: 720864

African (AFR) AF: 0.000451 AC: 15 AN: 33296

American (AMR) AF: 0.000513 AC: 22 AN: 42894

Ashkenazi Jewish (ASJ) AF: 0.000775 AC: 20 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.00 AC: 0 AN: 84750

European-Finnish (FIN) AF: 0.00112 AC: 58 AN: 51948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00387 AC: 4287 AN: 1107190

Other (OTH) AF: 0.00304 AC: 182 AN: 59928

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74496

African (AFR) AF: 0.000409 AC: 17 AN: 41578

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00164

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Mucopolysaccharidosis, MPS-III-B (2)
-	-	2	not provided (2)
-	-	1	Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.8
DANN	Benign	0.83
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism

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: rs151013014; hg19: chr17-40695884;