17-42544215-C-G

Variant names:

• chr17-42544215-C-G
• rs86312
• NM_000263.4:c.2209C>G

Variant summary

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

The NM_000263.4(NAGLU):​c.2209C>G​(p.Arg737Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 1,610,842 control chromosomes in the GnomAD database, including 676,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R737S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.85 (56290 hom., cov: 31)
  • Exomes 𝑓: 0.92 (619982 hom.)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.635
• Publications: 47 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.1667613E-7).
• BP6: Variant 17-42544215-C-G is Benign according to our data. Variant chr17-42544215-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	NM_000263.4	MANE Select	c.2209C>G	p.Arg737Gly	missense	Exon 6 of 6	NP_000254.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	ENST00000225927.7	TSL:1 MANE Select	c.2209C>G	p.Arg737Gly	missense	Exon 6 of 6	ENSP00000225927.1
	ENSG00000266929	ENST00000585572.1	TSL:4	n.379+5460C>G		intron	N/A
	NAGLU	ENST00000591587.1	TSL:5	c.*1178C>G		downstream_gene	N/A	ENSP00000467836.1

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129502 AN: 151990 Hom.: 56251 Cov.: 31

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.916

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.938

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.925

Gnomad OTH AF: 0.870

GnomAD2 exomes AF: 0.911 AC: 225684 AN: 247800 AF XY: 0.915

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.946

Gnomad ASJ exome AF: 0.929

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.874

Gnomad NFE exome AF: 0.922

Gnomad OTH exome AF: 0.911

GnomAD4 exome AF: 0.921 AC: 1343303 AN: 1458734 Hom.: 619982 Cov.: 74 AF XY: 0.922 AC XY: 668959 AN XY: 725748

African (AFR) AF: 0.652 AC: 21813 AN: 33480

American (AMR) AF: 0.942 AC: 42122 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.930 AC: 24298 AN: 26136

East Asian (EAS) AF: 0.999 AC: 39670 AN: 39698

South Asian (SAS) AF: 0.929 AC: 80091 AN: 86256

European-Finnish (FIN) AF: 0.878 AC: 44191 AN: 50310

Middle Eastern (MID) AF: 0.878 AC: 5066 AN: 5768

European-Non Finnish (NFE) AF: 0.927 AC: 1031071 AN: 1111986

Other (OTH) AF: 0.911 AC: 54981 AN: 60378

GnomAD4 genome AF: 0.852 AC: 129597 AN: 152108 Hom.: 56290 Cov.: 31 AF XY: 0.852 AC XY: 63363 AN XY: 74352

African (AFR) AF: 0.667 AC: 27632 AN: 41454

American (AMR) AF: 0.916 AC: 14002 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 3221 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5149 AN: 5162

South Asian (SAS) AF: 0.937 AC: 4518 AN: 4822

European-Finnish (FIN) AF: 0.871 AC: 9215 AN: 10576

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.926 AC: 62950 AN: 68016

Other (OTH) AF: 0.871 AC: 1844 AN: 2116

Alfa AF: 0.480 Hom.: 6616

Bravo AF: 0.855

TwinsUK AF: 0.934 AC: 3464

ALSPAC AF: 0.929 AC: 3580

ESP6500AA AF: 0.662 AC: 2916

ESP6500EA AF: 0.945 AC: 8124

ExAC AF: 0.905 AC: 109804

EpiCase AF: 0.919

EpiControl AF: 0.918

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Mucopolysaccharidosis, MPS-III-B (4)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Charcot-Marie-Tooth disease axonal type 2V (1)
-	-	1	Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.64
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.36
Sift	Benign	0.042	D
Sift4G	Benign	0.067	T
Polyphen		0.68	P
Vest4		0.14
MPC		0.60
ClinPred		0.013	T
GERP RS		4.0
Varity_R		0.21
gMVP		0.24
Mutation Taster		=93/7	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: rs86312; hg19: chr17-40696233; COSMIC: COSV56795682; COSMIC: COSV56795682;