rs149606212

Positions:

• chr7-65979854-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5 BP4 BS1_Supporting BS2

The NM_000181.4(GUSB):​c.454G>A​(p.Asp152Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,613,278 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D152G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: GUSB NM_000181.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications U:4 B:2 O:1
• Conservation: PhyloP100: 7.28

Genes affected

GUSB (HGNC:4696): (glucuronidase beta) This gene encodes a hydrolase that degrades glycosaminoglycans, including heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate. The enzyme forms a homotetramer that is localized to the lysosome. Mutations in this gene result in mucopolysaccharidosis type VII. Alternative splicing results in multiple transcript variants. There are many pseudogenes of this locus in the human genome.[provided by RefSeq, May 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29263932).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00126 (192/152218) while in subpopulation NFE AF= 0.00218 (148/67996). AF 95% confidence interval is 0.00189. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUSB	NM_000181.4	c.454G>A	p.Asp152Asn	missense_variant	3/12	ENST00000304895.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUSB	ENST00000304895.9	c.454G>A	p.Asp152Asn	missense_variant	3/12	1	NM_000181.4	P1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152098 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00115 AC: 287 AN: 249680 Hom.: 0 AF XY: 0.00118 AC XY: 159 AN XY: 135140

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.00187 AC: 2733 AN: 1461060 Hom.: 2 Cov.: 33 AF XY: 0.00179 AC XY: 1301 AN XY: 726778

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00189

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74428

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00160 Hom.: 1

Bravo AF: 0.00107

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00101 AC: 122

EpiCase AF: 0.00218

EpiControl AF: 0.00232

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Uncertain:4 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 7 Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
other, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2018	This variant is a known pseudodeficiency allele (PMID: 7573038, 19224584). Individuals with this variant can exhibit low beta-glucuronidase activity during enzyme analysis; however, it has been observed as homozygous in population databases and in individuals who did not have clinical evidence of muccopolysacchariduria (PMID: 7573038, 9490302). For these reasons, this variant has been classified as Benign (Pseudodeficiency allele). Pseudodeficiency allele
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2021	This variant is associated with the following publications: (PMID: 19224584, 7573038, 9490302, 34426522) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.024	D;T
Polyphen		0.94	P;.
Vest4		0.86
MVP		0.94
MPC		0.50
ClinPred		0.12	T
GERP RS		4.3
Varity_R		0.59
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149606212; hg19: chr7-65444841;